Incidence and Predictors for Recurrence of Ventricular Arrhythmia Presenting During Acute Myocarditis: A Multicenter Study.

BACKGROUND: Management of acute myocarditis (AM) patients experiencing ventricular arrhythmia (VA) during acute illness is controversial, especially regarding early implantable cardioverter-defibrillator (ICD) implantation. OBJECTIVES: The purpose of this study was to evaluate the prevalence of and find predictors for long-term sustained VA recurrence and overall mortality among AM patients with VA. METHODS: This was a multicenter retrospective analysis of AM patients (verified by cardiac magnetic resonance imaging or myocardial biopsy) with documented VA during the acute illness ("initial VA"). Patients with history of myocardial infarction, heart failure, or VA were excluded. The study endpoint was a composite of sustained VA and overall mortality during follow-up. RESULTS: The study included 69 AM patients with initial VA: sustained monomorphic ventricular tachycardia (MMVT) (n = 25), sustained polymorphic ventricular tachycardia (VT)/ventricular fibrillation (n = 13), and nonsustained VT (n = 31). Age was 44 ± 13 years, and 23 of 69 (33.3%) were women. During median follow-up of 5.5 years, 27 of 69 (39%) patients reached the composite endpoint including sustained VA (n = 24) and death (n = 11). Initial MMVT, predischarge left ventricular dysfunction (left ventricular ejection fraction <50%), and anteroseptal delayed enhancement on cardiac magnetic resonance imaging were significantly associated with the composite endpoint. On multivariable analysis, initial MMVT (HR: 5.17; 95% CI: 1.81-14.6; P = 0.001) and predischarge LV dysfunction (HR: 4.57; 95% CI: 1.83-11.5; P = 0.005) were independently associated with the composite endpoint. Using these 2 predictors, we could delineate subgroups with low (∼4%), medium (∼42%), and high (∼82%) 10-year incidence of composite endpoint. CONCLUSIONS: AM patients presenting with VA have high incidence of sustained VA recurrence and mortality posthospitalization. Initial MMVT and predischarge LV dysfunction are independently associated with VA recurrence and mortality. Implantable cardioverter-defibrillator implantation may be considered in such high-risk patients.

Ectopic multiple digit replantation salvage of hand torsion injury following anterolateral thigh perforator flap coverage.

Retrieval of four finger injury at proximal stump amputation with segmental injury along with soft tissue defect and impending compartment syndrome continues to be challenge for the surgeon. Immediate transplant considering temporary ectopic foster as a practical option in special case. We describe temporary ectopic finger implant for crush injury at Metacarpophalangeal (MCP level) with hand torsion along with forearm compartment was fostered to Dorsum of the foot. The torsion fingers was temporary fixed with mini external fixator for stabilization as salvage, ALT free flap was used to cover soft tissue defect of the hand. Replantation of survived figure was performed using the long pedicle to anatomical site without crushing the MCP joint to allow for later tendon transfer for finger. Satisfactory function regained with no foster site (foot) complication like pain or disability. The author validated ectopic foster for amputee as and procedure of choice for salvage of extremity under special circumstances.

Association of Pseudomonas aeruginosa incident infections with adherence to cystic fibrosis foundation care guidelines.

BACKGROUND: Care guidelines for cystic fibrosis (CF) have been developed to enhance consistent care and to improve health outcomes. We determined if adherence to CF care guidelines predicted P. aeruginosa incidence rates (Pa-IR) at U.S. CF centers in 2018. METHODS: This cross-sectional CF Foundation Patient Registry study included 82 adult and 132 pediatric centers. Adherence to 12 guidelines was defined categorically (guideline met) or as a continuous measure (proportion of patients being treated/evaluated per guideline). Association of adherence to individual guidelines with Pa-IR, accounted for center and patient characteristics relevant to Pa-IR and were modeled using random forests and weighted-least-squares (WLS) analyses. RESULTS: The mean Pa-IR was 0.2 cases/patient-years at risk (SE 0.0074) for all centers combined. Guideline adherence was lowest for ≥4 bacterial cultures/year (54% of centers) and annual oral glucose tolerance test (OGTT) (48% of centers), and highest for annual non-tuberculous mycobacteria (NTM) sputum culture (98%). The mean number of guidelines met was 6.7 and higher for pediatric (7.3) than adult (5.6) centers, (p<0.001). The number of guidelines met correlated negatively with Pa-IR (ß=-0.007, p = 0.043). Macrolide prescription and annual OGTT per guideline were associated with lower and higher Pa-IR, respectively. Centers with lower center-wide lung function, higher proportion of pwCF with low body-mass index, and location in the Southwest had higher Pa-IR. CONCLUSION: Overall adherence to guidelines was high except for performing ≥4 bacterial cultures/year and OGTT. Higher Pa-IR was associated with center characteristics and lower guideline adherence. The lower Pa-IR with greater adherence to guidelines suggests that focusing on quality care can positively impact Pa-IR.

Papillary glioneuronal tumor presenting with low-pressure hydrocephalus from intraventricular spread: Case Report.

Papillary glioneuronal tumors are a rare and typically benign entity with pathological and radiographic complexity. Presentation can mimic other neoplasms, making diagnosis more challenging. The literature to date describes the clinical understanding, diagnostic, therapeutic, and prognostic characteristics of this limited number of patients. In this article, we report an unusual case of a glioneuronal tumor with multifocal presentation, normal pressure hydrocephalus-like symptoms, and large peritumoral parenchymal cysts, which guided the surgical approach. This unusual presentation has not previously been reported and adds valuable information to the clinical recognition and management literature.

Developing a Formulation Strategy Coupled with PBPK Modeling and Simulation for the Weakly Basic Drug Albendazole.

Albendazole (ABZ) is a weakly basic drug that undergoes extensive presystemic metabolism after oral administration and converts to its active form albendazole sulfoxide (ABZ_SO). The absorption of albendazole is limited by poor aqueous solubility, and dissolution is the rate-limiting step in the overall exposure of ABZ_SO. In this study, PBPK modeling was used to identify formulation-specific parameters that impact the oral bioavailability of ABZ_SO. In vitro experiments were carried out to determine pH solubility, precipitation kinetics, particle size distribution, and biorelevant solubility. A transfer experiment was conducted to determine the precipitation kinetics. A PBPK model for ABZ and ABZ_SO was developed using the Simcyp™ Simulator based on parameter estimates from in vitro experiments. Sensitivity analyses were performed to assess the impact of physiological parameters and formulation-related parameters on the systemic exposure of ABZ_SO. Model simulations predicted that increased gastric pH significantly reduced ABZ absorption and, subsequently, ABZ_SO systemic exposure. Reducing the particle size below 50 µm did not improve the bioavailability of ABZ. Modeling results illustrated that systemic exposure of ABZ_SO was enhanced by increasing solubility or supersaturation and decreasing the drug precipitation of ABZ at the intestinal pH level. These results were used to identify potential formulation strategies to enhance the oral bioavailability of ABZ_SO.

Statistically Adjusting for Wear Time in Randomized Trials of Continuous Glucose Monitors as a Complement to Intent-to-Treat and As-Treated Analyses: Application and Evaluation in Two Trials.

Background: Randomized trials of continuous glucose monitoring (CGM) often estimate treatment effects using standard intent-to-treat (ITT) analyses. We explored how adjusting for CGM-measured wear time could complement existing analyses by estimating the effect of receiving and using CGM 100% of the time. Methods: We analyzed data from two 6-month CGM trials spanning diverse ages, the Wireless Innovation for Seniors with Diabetes Mellitus (WISDM) and CGM Intervention in Teens and Young Adults with Type 1 Diabetes (CITY) Studies. To adjust the ITT estimates for CGM use, as measured by wear time, we used an instrumental variable (IV) approach with the treatment assignment as an instrument. Outcomes included (1) time in range ([TIR] 70-180 mg/dL), time below range ([TBR] ≤70 mg/dL), and time above range ([TAR] ≥250 mg/dL). We estimated outcomes based on CGM use in the last 28 days of the trial and the full trial. Findings: In the WISDM study, the wear time rates over the 28-day window and full trial period were 93.1% (standard deviation [SD]: 20.4) and 94.5% (SD: 11.9), respectively. In the CITY study, the wear time rates over the 28-day window and full trial period were 82.2% (SD: 26.5) and 83.1% (SD: 21.5), respectively. IV-based estimates for the effect of CGM on TIR, TBR, and TAR suggested greater improvements in glycemic management than the ITT counterparts. The magnitude of the differences was proportional to the level of wear time observed in the trials. Interpretation: In trials of CGM use, the effect of variable wear time is non-negligible. By providing adherence-adjusted estimates, the IV approach may have additional utility for individual clinical decision-making.

Estimation of a Machine Learning-Based Decision Rule to Reduce Hypoglycemia Among Older Adults With Type 1 Diabetes: A Post Hoc Analysis of Continuous Glucose Monitoring in the WISDM Study.

BACKGROUND: The Wireless Innovation for Seniors with Diabetes Mellitus (WISDM) study demonstrated continuous glucose monitoring (CGM) reduced hypoglycemia over 6 months among older adults with type 1 diabetes (T1D) compared with blood glucose monitoring (BGM). We explored heterogeneous treatment effects of CGM on hypoglycemia by formulating a data-driven decision rule that selects an intervention (ie, CGM vs BGM) to minimize percentage of time <70 mg/dL for each individual WISDM participant. METHOD: The precision medicine analyses used data from participants with complete data (n = 194 older adults, including those who received CGM [n = 100] and BGM [n = 94] in the trial). Policy tree and decision list algorithms were fit with 14 baseline demographic, clinical, and laboratory measures. The primary outcome was CGM-measured percentage of time spent in hypoglycemic range (<70 mg/dL), and the decision rule assigned participants to a subgroup reflecting the treatment estimated to minimize this outcome across all follow-up visits. RESULTS: The optimal decision rule was found to be a decision list with 3 steps. The first step moved WISDM participants with baseline time-below range >1.35% and no detectable C-peptide levels to the CGM subgroup (n = 139), and the second step moved WISDM participants with a baseline time-below range of >6.45% to the CGM subgroup (n = 18). The remaining participants (n = 37) were left in the BGM subgroup. Compared with the BGM subgroup (n = 37; 19%), the group for whom CGM minimized hypoglycemia (n = 157; 81%) had more baseline hypoglycemia, a lower proportion of detectable C-peptide, higher glycemic variability, longer disease duration, and higher proportion of insulin pump use. CONCLUSIONS: The decision rule underscores the benefits of CGM for older adults to reduce hypoglycemia. Diagnostic CGM and laboratory markers may inform decision-making surrounding therapeutic CGM and identify older adults for whom CGM may be a critical intervention to reduce hypoglycemia.

Glasgow Coma Scale Motor Score Predicts Need for Tracheostomy After Decompressive Craniectomy for Traumatic Brain Injury.

Objective: Many patients with severe traumatic brain injury (TBI) require a tracheostomy after decompressive craniectomy. Determining which patients will require tracheostomy is often challenging. The existing methods for predicting which patients will require tracheostomy are more applicable to stroke and spontaneous intracranial hemorrhage. The aim of this study was to investigate whether the Glasgow Coma Scale (GCS) motor score can be used as a screening method for predicting which patients who undergo decompressive craniectomy for severe TBI are likely to require tracheostomy. Methods: The neurosurgery census at the University of Kansas Medical Center was retrospectively reviewed to identify adult patients aged over 18 years who underwent decompressive craniectomy for TBI. Eighty patients met the inclusion criteria for the study. There were no exclusion criteria. The primary outcome of interest was the need for tracheostomy. The secondary outcome was the comparison of the total length of stay (LOS) and intensive care unit LOS between the early and late tracheostomy patient groups. Results: All patients (100%) with a GCS motor score of 4 or less on post operative (POD) 5 required tracheostomy. Setting the threshold at GCS motor score of 5 on POD 5 for recommending tracheostomy resulted in 86.7% sensitivity, 91.7% specificity, and 90.5% positive predictive value, with an area under the receiver operator curve of 0.9101. Conclusion: GCS motor score of 5 or less on POD 5 of decompressive craniectomy is a useful screening threshold for selecting patients who may benefit from tracheostomy, or may be potential candidates for extubation.

Stabilized direct learning for efficient estimation of individualized treatment rules.

In recent years, the field of precision medicine has seen many advancements. Significant focus has been placed on creating algorithms to estimate individualized treatment rules (ITRs), which map from patient covariates to the space of available treatments with the goal of maximizing patient outcome. Direct learning (D-Learning) is a recent one-step method which estimates the ITR by directly modeling the treatment-covariate interaction. However, when the variance of the outcome is heterogeneous with respect to treatment and covariates, D-Learning does not leverage this structure. Stabilized direct learning (SD-Learning), proposed in this paper, utilizes potential heteroscedasticity in the error term through a residual reweighting which models the residual variance via flexible machine learning algorithms such as XGBoost and random forests. We also develop an internal cross-validation scheme which determines the best residual model among competing models. SD-Learning improves the efficiency of D-Learning estimates in binary and multi-arm treatment scenarios. The method is simple to implement and an easy way to improve existing algorithms within the D-Learning family, including original D-Learning, Angle-based D-Learning (AD-Learning), and Robust D-learning (RD-Learning). We provide theoretical properties and justification of the optimality of SD-Learning. Head-to-head performance comparisons with D-Learning methods are provided through simulations, which demonstrate improvement in terms of average prediction error (APE), misclassification rate, and empirical value, along with a data analysis of an acquired immunodeficiency syndrome (AIDS) randomized clinical trial.

Evaluation of Pulse Rate, Oxygen Saturation, and Respiratory Effort after Different Types of Feeding Methods in Preterm Newborns.

Background: During the initial days of hospitalization, preterm newborns are given combinations of breastfeeding, spoon/paladai feeding, and/or gavage feeding. Each method of feeding may have a different effect on vital parameters. Objective: To study changes in vital parameters in relation to different feeding methods and postmenstrual age (PMA) in preterm newborns. Study Design. This prospective observational study was carried out at a tertiary care neonatal unit. Participants. Physiologically stable preterm newborns with PMA less than 37 weeks on full enteral feeds were included in the study. Intervention. None. Outcomes. Respiratory rate (RR), pulse rate (PR), oxygen saturation (SPO2), nasal flaring, and lower chest indrawing were monitored before and up to 3 h after the breastfeeding/spoon (paladai) feeding/gavage feeding or their combinations. These vital parameters were assessed in relation to the feeding methods and PMA groups using ANOVA. Results: A total of 383 records were analyzed from 110 newborns. No infant developed chest indrawing or nasal flaring after any feeding method. During the 3 h period of monitoring, vital parameters changed significantly except in the gavage feeding group. The mean PR did not change, but the mean RR and SPO2 changed significantly at different PMA. Conclusion: Vital parameters changed after different types of feeding methods and at different PMA. A further multicentric prospective study is needed to understand the effect of different feeding methods and PMA on vital parameters.

Current Practices, Gap Analysis, and Proposed Workflows for PBPK Modeling of Cytochrome P450 Induction: An Industry Perspective.

The International Consortium for Innovation and Quality (IQ) Physiologically Based Pharmacokinetic (PBPK) Modeling Induction Working Group (IWG) conducted a survey across participating companies around general strategies for PBPK modeling of induction, including experience with its utility to address various questions, regulatory interactions, and regulatory acceptance. The results highlight areas where PBPK modeling is used with high confidence and identifies opportunities where confidence is lower and further evaluation is needed. To enhance the survey results, the PBPK-IWG also collected case studies and analyzed recent literature examples where PBPK models were applied to predict CYP3A induction-mediated drug-drug interactions. PBPK modeling of induction has evolved and progressed significantly, proving to have great potential to accelerate drug discovery and development. With the aim of enabling optimal use for new molecular entities that are either substrates and/or inducers of CYP3A, the PBPK-IWG proposes initial workflows for PBPK application, discusses future trends, and identifies gaps that need to be addressed.

Barriers implementing infection prevention and control experienced by healthcare workers, people with CF and parents.

BACKGROUND: Barriers to implementing infection prevention and control (IP&C) practices may be experienced by healthcare workers (HCWs) caring for people with CF (PwCF), PwCF, and their families. We hypothesized that these stakeholders from CF centers with early adoption of the updated 2013 IP&C guideline would experience fewer barriers implementing selected recommendations compared to stakeholders from CF centers with delayed adoption. METHODS: In 2018-2019 we surveyed HCWs and PwCF/parents from 25 CF centers to identify knowledge, attitude, and practice barriers. Each center recruited five HCWs with different occupations. Pediatric centers recruited five parents of children <18 years old and five young adults 18-21 years old. Adult centers recruited 10 adults ≥18 years old. We determined respondents' knowledge scores, the proportion who agreed with or perceived health benefits from recommendations, and reported adherence to recommendations. RESULTS: Knowledge scores, perception of health benefits, and adherence to selected practices were similar among participants from centers with early vs. delayed adoption, yet generally lower for inpatient nurses. IP&C practitioners were less likely to perceive health benefits from PwCF wearing masks and HCWs wearing gowns and gloves. Among HCWs, 57% educated >75% of PwCF/parents about IP&C and 43% advised >75% of PwCF/parents to avoid socializing with other PwCF. Among PwCF/parents, 69%, 53%, and 56% reported discussions with their care teams about performing hand hygiene, avoiding socialization, or the 2013 IP&C guideline, respectively. CONCLUSIONS: Our findings suggest opportunities for targeted education for specific HCW occupations and for PwCF and their families.

Development and validation of multivariable prediction models for adverse COVID-19 outcomes in patients with IBD.

OBJECTIVES: Develop an individualised prognostic risk prediction tool for predicting the probability of adverse COVID-19 outcomes in patients with inflammatory bowel disease (IBD). DESIGN AND SETTING: This study developed and validated prognostic penalised logistic regression models using reports to the international Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease voluntary registry from March to October 2020. Model development was done using a training data set (85% of cases reported 13 March-15 September 2020), and model validation was conducted using a test data set (the remaining 15% of cases plus all cases reported 16 September-20 October 2020). PARTICIPANTS: We included 2709 cases from 59 countries (mean age 41.2 years (SD 18), 50.2% male). All submitted cases after removing duplicates were included. PRIMARY AND SECONDARY OUTCOME MEASURES: COVID-19 related: (1) Hospitalisation+: composite outcome of hospitalisation, ICU admission, mechanical ventilation or death; (2) Intensive Care Unit+ (ICU+): composite outcome of ICU admission, mechanical ventilation or death; (3) Death. We assessed the resulting models' discrimination using the area under the curve of the receiver operator characteristic curves and reported the corresponding 95% CIs. RESULTS: Of the submitted cases, a total of 633 (24%) were hospitalised, 137 (5%) were admitted to the ICU or intubated and 69 (3%) died. 2009 patients comprised the training set and 700 the test set. The models demonstrated excellent discrimination, with a test set area under the curve (95% CI) of 0.79 (0.75 to 0.83) for Hospitalisation+, 0.88 (0.82 to 0.95) for ICU+ and 0.94 (0.89 to 0.99) for Death. Age, comorbidities, corticosteroid use and male gender were associated with a higher risk of death, while the use of biological therapies was associated with a lower risk. CONCLUSIONS: Prognostic models can effectively predict who is at higher risk for COVID-19-related adverse outcomes in a population of patients with IBD. A free online risk calculator (https://covidibd.org/covid-19-risk-calculator/) is available for healthcare providers to facilitate discussion of risks due to COVID-19 with patients with IBD.

Complicated Chikungunya Infection in Tertiary ICU in Western India - A Prospective Study Over 3 Years.

BACKGROUND: Chikungunya is a globally spreading infectious arboviral disease transmitted from a diurnal bite of the Aedes aegypti and Aedes albopictus Mosquitoes. It is a disease with sporadic outbreaks. It is now resurfacing in South East Asia especially in India, where it is found to have high mortality and morbidity and presenting with atypical presentation, especially with the neurotropic presentation. OBJECTIVE: To review clinical profile of patients who required admission in the Intensive care unit with atypical presentation of Chikungunya and to study their clinical spectrum and outcome over a course of three years in India. METHOD AND FINDINGS: Using Established guidelines, we conducted a prospective study in a Tertiary care center where we identified patients who required intensive care admissions and were admitted with complicated chikungunya infection and then evaluated their clinical progression of the disease. CONCLUSION: CHIKV infection is rapidly emerging in more than 100 countries and more and more atypical serious neurological manifestations are seen in elderly populations. Many of these patients have high morbidity and mortality.

Age-Related Changes in Pediatric Physiology: Quantitative Analysis of Organ Weights and Blood Flows : Age-Related Changes in Pediatric Physiology.

Development of comprehensive and updated quantitative relationships between physiological parameters and age for pediatrics remains to be accomplished. Towards this goal, we have performed a thorough literature search and collected published data on organ weights and organ blood flow rates for 0-20-year-old male and female human subjects. The data were used to develop continuous relationships between physiological parameters and age, using a single form of mathematical equation. Four sets of equations (0-2 years male, 0-2 years female, 2-20 years male, 2-20 years female) for the body weight vs. age, height vs. age, and organ weight vs. age relationships and 2 sets of equations (0-20 years male, 0-20 years female) for organ flow rate vs. age relationship were developed. The variability of each physiological parameter was also estimated, and the equations allow simulation of a virtual population for a specific age, weight, and sex. We further compared the physiological parameters vs. age curves simulated using our equations to the existing databases (Simcyp Simulator and PK-Sim). The predicted physiological parameters were comparable between our study and the existing databases, validating our equation's utility. Additionally, we described body weight-normalized organ weights and organ blood flow rates as a function of age, to provide an insight into how the contribution of each organ towards total body weight and total blood flow changes throughout ontogenesis. The physiological parameter database and equations presented here can serve as an open source to facilitate the development of pediatric physiologically based pharmacokinetic models.

Development and validation of multivariable prediction models for adverse COVID-19 outcomes in IBD patients.

IMPORTANCE: Risk calculators can facilitate shared medical decision-making 1 . Demographics, comorbidities, medication use, geographic region, and other factors may increase the risk for COVID-19-related complications among patients with IBD 2,3 . OBJECTIVES: Develop an individualized prognostic risk prediction tool for predicting the probability of adverse COVID-19 outcomes in patients with IBD. DESIGN SETTING AND PARTICIPANTS: This study developed and validated prognostic penalized logistic regression models 4 using reports to Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) from March-October 2020. Model development was done using a training data set (85% of cases reported March 13 - September 15, 2020), and model validation was conducted using a test data set (the remaining 15% of cases plus all cases reported September 16-October 20, 2020). MAIN OUTCOMES AND MEASURES: COVID-19 related:Hospitalization+: composite outcome of hospitalization, ICU admission, mechanical ventilation, or deathICU+: composite outcome of ICU admission, mechanical ventilation, or deathDeathWe assessed the resulting models' discrimination using the area under the curve (AUC) of the receiver-operator characteristic (ROC) curves and reported the corresponding 95% confidence intervals (CIs). RESULTS: We included 2709 cases from 59 countries (mean age 41.2 years [s.d. 18], 50.2% male). A total of 633 (24%) were hospitalized, 137 (5%) were admitted to the ICU or intubated, and 69 (3%) died. 2009 patients comprised the training set and 700 the test set.The models demonstrated excellent discrimination, with a test set AUC (95% CI) of 0.79 (0.75, 0.83) for Hospitalization+, 0.88 (0.82, 0.95) for ICU+, and 0.94 (0.89, 0.99) for Death. Age, comorbidities, corticosteroid use, and male gender were associated with higher risk of death, while use of biologic therapies was associated with a lower risk. CONCLUSIONS AND RELEVANCE: Prognostic models can effectively predict who is at higher risk for COVID-19-related adverse outcomes in a population of IBD patients. A free online risk calculator ( https://covidibd.org/covid-19-risk-calculator/ ) is available for healthcare providers to facilitate discussion of risks due to COVID-19 with IBD patients. The tool numerically and visually summarizes the patient's probabilities of adverse outcomes and associated CIs. Helping physicians identify their highest-risk patients will be important in the coming months as cases rise in the US and worldwide. This tool can also serve as a model for risk stratification in other chronic diseases. KEY POINTS: Question: How well can a multivariable risk model predict the risk of hospitalization, intensive care unit (ICU) stay, or death due to COVID-19 in patients with inflammatory bowel disease (IBD)?Findings: Multivariable prediction models developed using data from an international voluntary registry of IBD patients and available for use online ( https://covidibd.org/ ) have very good discrimination for predicting hospitalization (Test set AUC 0.79) and excellent discrimination for ICU admission (Test set AUC 0.88) and death (Test set AUC 0.94). The models were developed with a training sample of 2009 cases and validated in an independent test sample of 700 cases comprised of a random sub-sample of cases and all cases entered in the registry during a one-month period after model development. Meaning: This risk prediction model may serve as an effective tool for healthcare providers to facilitate conversations about COVID-19-related risks with IBD patients.

Live-Streaming Surgery for Medical Student Education - Educational Solutions in Neurosurgery During the COVID-19 Pandemic.

OBJECTIVE: The COVID-19 pandemic significantly altered medical student education. The ability for students to be a part of the operating room team was highly restricted. Technology can be used to ensure ongoing surgical education during this time of limited in-person educational opportunities. DESIGN: We have developed an innovative solution of securely live-streaming surgery with real-time communication between the surgeon and students to allow for ongoing education during the pandemic. RESULTS: We successfully live-streamed multiple different types of neurosurgical operations utilizing multiple video sources. This method uses inexpensive, universal equipment that can be implemented at any institution to enable virtual education of medical students and other learners. CONCLUSIONS: This technology has facilitated education during this challenging time. This technological set-up for live-streaming surgery has the potential of improving medical and graduate medical education in the future.

On the length scale dependence of DNA conformational change under local perturbation.

Conformational change of a DNA molecule is frequently observed in multiple biological processes and has been modeled using a chain of strongly coupled oscillators with a nonlinear bistable potential. While the mechanism and properties of conformational change in the model have been investigated and several reduced order models developed, the conformational dynamics as a function of the length of the oscillator chain is relatively less clear. To address this, we use a modified Lindstedt-Poincare method and numerical computations. We calculate a perturbation expansion of the frequency of the model's nonzero modes, finding that approximating these modes with their unperturbed dynamics, as in a previous reduced order model, may not hold when the length of the DNA model increases. We investigate the conformational change to the local perturbation in models of varying lengths, finding that for the chosen input and parameters, there are two regions of DNA length in the model - first, where the minimum energy required to undergo the conformational change increases with the DNA length; and second, where it is almost independent of the length of the DNA model. We analyze the conformational change in these models by adding randomness to the local perturbation, finding that the tendency of the system to remain in a stable conformation against random perturbation decreases with increase in DNA length. These results should help to understand the role of the length of a DNA molecule in influencing its conformational dynamics.

Correction to: Physiologically Based Pharmacokinetic Modeling of CFTR Modulation in People with Cystic Fibrosis Transitioning from Mono or Dual Regimens to Triple-Combination Elexacaftor/Tezacaftor/Ivacaftor.

The original version of this article unfortunately contained a mistake.

Physiologically Based Pharmacokinetic Modeling of CFTR Modulation in People with Cystic Fibrosis Transitioning from Mono or Dual Regimens to Triple-Combination Elexacaftor/Tezacaftor/Ivacaftor.

INTRODUCTION: The triple-combination (TC) cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen elexacaftor, tezacaftor, and ivacaftor was shown to be safe and efficacious in phase 3 trials of people with cystic fibrosis (pwCF) ≥ 12 years of age with ≥ 1 F508del-CFTR allele. Here, a simulation study predicted ivacaftor, tezacaftor, and elexacaftor exposures and impacts on CFTR modulation following transition from ivacaftor [a cytochrome P450 3A (CYP3A) substrate], lumacaftor (a CYP3A inducer)/ivacaftor, or tezacaftor/ivacaftor to TC. METHODS: Physiologically based pharmacokinetic (PBPK) modeling was used to evaluate plasma exposures during transition from mono- or dual-combination CFTR modulator regimens to TC. PBPK models were parameterized using data from human hepatocytes to account for CYP3A induction by lumacaftor and validated to match clinical data from healthy volunteers and pwCF. Using dosing regimens for pwCF ≥ 12 years of age, simulations were performed for ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor dosing for 14 days followed by immediate transition to elexacaftor/tezacaftor/ivacaftor dosing for 14 days. Drug exposures during transitions were compared with respective half-maximal effective concentrations (EC50) estimated from efficacy endpoint data from clinical studies. RESULTS: In simulations of immediate transition from ivacaftor or tezacaftor/ivacaftor to TC, the preceding treatment had no impact on ivacaftor, tezacaftor, or elexacaftor exposures. In simulations of immediate transition from lumacaftor/ivacaftor to TC, ivacaftor exposure decreased to 64% of maximum effective concentration (EC), due to reduction in ivacaftor dose and residual CYP3A4 induction, then returned to 90-95% of maximum EC. Lumacaftor-mediated CYP3A induction resolved within approximately 2 weeks. In all simulations, ivacaftor, tezacaftor, and elexacaftor exposures approached steady state within 2 weeks following transition and, at all times, ivacaftor and ≥ 1 CFTR corrector remained above EC50. CONCLUSION: PBPK modeling indicates that immediate transition to the elexacaftor/tezacaftor/ivacaftor regimen from an ivacaftor, lumacaftor/ivacaftor, or tezacaftor/ivacaftor regimen results in sustained CFTR modulation in pwCF ≥ 12 years of age.