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.

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.

Equilibration of energy in slow-fast systems.

Ergodicity is a fundamental requirement for a dynamical system to reach a state of statistical equilibrium. However, in systems with several characteristic timescales, the ergodicity of the fast subsystem impedes the equilibration of the whole system because of the presence of an adiabatic invariant. In this paper, we show that violation of ergodicity in the fast dynamics can drive the whole system to equilibrium. To show this principle, we investigate the dynamics of springy billiards, which are mechanical systems composed of a small particle bouncing elastically in a bounded domain, where one of the boundary walls has finite mass and is attached to a linear spring. Numerical simulations show that the springy billiard systems approach equilibrium at an exponential rate. However, in the limit of vanishing particle-to-wall mass ratio, the equilibration rates remain strictly positive only when the fast particle dynamics reveal two or more ergodic components for a range of wall positions. For this case, we show that the slow dynamics of the moving wall can be modeled by a random process. Numerical simulations of the corresponding springy billiards and their random models show equilibration with similar positive rates.

RalA is overactivated in medulloblastoma.

Medulloblastoma (MDB) represents a major form of malignant brain tumors in the pediatric population. A vast spectrum of research on MDB has advanced our understanding of the underlying mechanism, however, a significant need still exists to develop novel therapeutics on the basis of gaining new knowledge about the characteristics of cell signaling networks involved. The Ras signaling pathway, one of the most important proto-oncogenic pathways involved in human cancers, has been shown to be involved in the development of neurological malignancies. We have studied an important effector down-stream of Ras, namely RalA (Ras-Like), for the first time and revealed overactivation of RalA in MDB. Affinity precipitation analysis of active RalA (RalA-GTP) in eight MDB cell lines (DAOY, RES256, RES262, UW228-1, UW426, UW473, D283 and D425) revealed that the majority contained elevated levels of active RalA (RalA-GTP) as compared with fetal cerebellar tissue as a normal control. Additionally, total RalA levels were shown to be elevated in 20 MDB patient samples as compared to normal brain tissue. The overall expression of RalA, however, was comparable in cancerous and normal samples. Other important effectors of RalA pathway including RalA binding protein-1 (RalBP1) and protein phosphatase A (PP2A) down-stream of Ral and Aurora kinase A (AKA) as an upstream RalA activator were also investigated in MDB. Considering the lack of specific inhibitors for RalA, we used gene specific silencing in order to inhibit RalA expression. Using a lentivirus expressing anti-RalA shRNA we successfully inhibited RalA expression in MDB and observed a significant reduction in proliferation and invasiveness. Similar results were observed using inhibitors of AKA and geranyl-geranyl transferase (non-specific inhibitors of RalA signaling) in terms of loss of in vivo tumorigenicity in heterotopic nude mouse model. Finally, once tested in cells expressing CD133 (a marker for MDB cancer stem cells), higher levels of RalA activation was observed. These data not only bring RalA to light as an important contributor to the malignant phenotype of MDB but introduces this pathway as a novel target in the treatment of this malignancy.

KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia.

We describe a mutation (E299V) in KCNJ2, the gene that encodes the strong inward rectifier K(+) channel protein (Kir2.1), in an 11-y-old boy. The unique short QT syndrome type-3 phenotype is associated with an extremely abbreviated QT interval (200 ms) on ECG and paroxysmal atrial fibrillation. Genetic screening identified an A896T substitution in a highly conserved region of KCNJ2 that resulted in a de novo mutation E299V. Whole-cell patch-clamp experiments showed that E299V presents an abnormally large outward IK1 at potentials above -55 mV (P < 0.001 versus wild type) due to a lack of inward rectification. Coexpression of wild-type and mutant channels to mimic the heterozygous condition still resulted in a large outward current. Coimmunoprecipitation and kinetic analysis showed that E299V and wild-type isoforms may heteromerize and that their interaction impairs function. The homomeric assembly of E299V mutant proteins actually results in gain of function. Computer simulations of ventricular excitation and propagation using both the homozygous and heterozygous conditions at three different levels of integration (single cell, 2D, and 3D) accurately reproduced the electrocardiographic phenotype of the proband, including an exceedingly short QT interval with merging of the QRS and the T wave, absence of ST segment, and peaked T waves. Numerical experiments predict that, in addition to the short QT interval, absence of inward rectification in the E299V mutation should result in atrial fibrillation. In addition, as predicted by simulations using a geometrically accurate three-dimensional ventricular model that included the His-Purkinje network, a slight reduction in ventricular excitability via 20% reduction of the sodium current should increase vulnerability to life-threatening ventricular tachyarrhythmia.

Intracerebral laser interstitial thermal therapy followed by tumor resection to minimize cerebral edema.

OBJECTIVE Laser interstitial thermal therapy (LITT) is used in numerous neurosurgical applications including lesions that are difficult to resect. Its rising popularity can be attributed to its minimally invasive approach, improved accuracy with real-time MRI guidance and thermography, and enhanced control of the laser. One of its drawbacks is the possible development of significant edema, which contributes to extended hospital stays and often necessitates hyperosmolar or steroid therapy. Here, the authors discuss the use of minimally invasive craniotomy to resect tissue ablated with LITT in attempt to minimize cerebral edema. METHODS Five patients with glioblastoma multiforme prospectively underwent LITT followed by resection. The LITT was performed with the aid of an MR-compatible skull-mounted frame in the MRI suite. Ablated tumor was then resected via small craniotomy by using the NICO Myriad system or cavitron ultrasonic surgical aspirator. Postoperative management involved dexamethasone administration slowly tapered over several weeks. RESULTS The use of resection following LITT, as compared with open resection or LITT alone, did not extend the hospital stay except in 1 patient who required 3-day inpatient management of edema with a trapped ventricle. No new neurological deficits were encountered, although 1 patient developed seizures postoperatively. No increase in infection rates was identified. CONCLUSIONS Resection of ablated tumor is a viable option to reduce the incidence of neurological deficits due to edema following LITT. This approach appears to mitigate cerebral edema by increasing available volume for mass effect and reducing the tissue burden that may promote an inflammatory response.

Neural basis of non-conscious visual working memory.

Recent research indicates that human observers can perform high-level cognitive tasks typically associated with working memory processes (e.g. learning of complex item sequences, reading, arithmetic or delayed visual discrimination) independently of conscious awareness of the relevant information. However, the neural basis of this phenomenon is not known. Here we show neuroimaging and neurostimulation evidence that the dorsolateral and anterior prefrontal cortex can operate on non-conscious information in a manner that goes beyond automatic forms of sensorimotor priming and which may support implicit working memory processes and higher-level cognitive function.

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.

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.

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.

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.

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.

All-epiphyseal ACL reconstruction improves tibiofemoral contact: an in vitro study.

BACKGROUND: Anterior cruciate ligament (ACL) injury alters tibiofemoral contact during function, with a posterior shift of the point of contact on the tibia. An all-epiphyseal approach to ACL reconstruction is performed in pediatric patients to improve tibiofemoral contact without disturbing the physis. The hypothesis of the study is that all-epiphyseal ACL reconstruction will shift contact anteriorly on the tibia, as compared with the ACL-deficient knee. METHODS: Ten cadaver knees were tested with the ACL cut and with an all-epiphyseal reconstruction. The knees were set at multiple flexion angles (0, 15, 30, and 45 degrees) and loaded with a quadriceps force of 596 N in combination with an anterior force of 100 N, with the quadriceps loaded in isolation, and with the quadriceps loaded in combination with a hamstrings force of 200 N. Sensors under the menisci characterized the center of force on the tibia. Paired t tests were used to identify significant (P<0.05) differences between the reconstructed and cut conditions for all loading conditions at all flexion angles. RESULTS: On the medial plateau, the average center of force was 2 to 5 mm more anterior for the reconstructed condition than for the ACL cut, with the difference significant for all test conditions. The largest differences between the ACL conditions occurred for the combination of quadriceps forces plus an anterior force. On the lateral plateau, the anterior shift in the center of force from the ACL cut to reconstructed condition was significant for all flexion angles except 0 degree for all loading conditions, with an average difference of approximately 2 mm for all significant differences. CONCLUSIONS: All-epiphyseal ACL reconstruction shifts contact anteriorly on the tibia compared with the injured knee. CLINICAL RELEVANCE: The anterior shift of contact on the femur related to all-epiphyseal ACL reconstruction reduces changes related to ACL injury, which could reduce the risk of cartilage damage and meniscal injuries without violating the growth plate in pediatric patients.

Limited benefit of hamstrings forces for the anterior cruciate ligament-deficient knee: an in vitro study.

The hamstrings are considered stabilizers of the anterior cruciate ligament-deficient knee; however, anterior cruciate ligament injury primarily influences tibiofemoral kinematics near full extension, where the hamstrings have the least influence on kinematics. Ten knees were tested at multiple flexion angles in vitro to directly compare the influence of anterior cruciate ligament injury and hamstrings activation on tibiofemoral kinematics. Tibiofemoral kinematics were measured for three testing conditions: (1) anterior cruciate ligament intact, with forces applied through the quadriceps muscles (596 N), (2) anterior cruciate ligament cut, with forces applied through the quadriceps, and (3) anterior cruciate ligament cut, with forces applied through the quadriceps and hamstrings (200 N). Based on repeated measures comparisons performed at each flexion angle, cutting the anterior cruciate ligament significantly (p < 0.05) increased tibial anterior translation, medial translation, and internal rotation at 0 degrees and 15 degrees of flexion by approximately 2.5 mm, 1 mm, and 2 degrees, respectively. Internal rotation also increased significantly at 30 degrees. With the anterior cruciate ligament cut, loading the hamstrings significantly decreased anterior translation, medial translation, and internal rotation at 45 degrees, by approximately 2 mm, 2 mm, and 4 degrees, respectively. Loading the hamstrings caused kinematic changes in the opposite direction of the anterior cruciate ligament injury, but the changes occurred at deeper flexion angles than those at which anterior cruciate ligament injury influenced tibiofemoral kinematics.

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.

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.