A feasibility randomized controlled trial of a NICU rehabilitation program for very low birth weight infants.

Motor disability is common in children born preterm. Interventions focusing on environmental enrichment and emotional connection can positively impact outcomes. The NICU-based rehabilitation (NeoRehab) program consists of evidence-based interventions provided by a parent in addition to usual care. The program combines positive sensory experiences (vocal soothing, scent exchange, comforting touch, skin-to-skin care) as well as motor training (massage and physical therapy) in a gestational age (GA) appropriate fashion. To investigate the acceptability, feasibility and fidelity of the NeoRehab program in very low birthweight (VLBW) infants. All interventions were provided by parents in addition to usual care. Infants (≤ 32 weeks' GA and/or ≤ 1500 g birthweight) were enrolled in a randomized controlled trial comparing NeoRehab to usual care (03/2019-10/2020). The a priori dosing goal was for interventions to be performed 5 days/week. The primary outcomes were the acceptability, feasibility and fidelity of the NeoRehab program. 36 participants were randomized to the intervention group and 34 allocated to usual care. The recruitment rate was 71% and retention rate 98%. None of the interventions met the 5 days per week pre-established goal. 97% of participants documented performing a combination of interventions at least 3 times per week. The NeoRehab program was well received and acceptable to parents of VLBW infants. Programs that place a high demand on parents (5 days per week) are not feasible and goals of intervention at least 3 times per week appear to be feasible in the context of the United States. Parent-provided motor interventions were most challenging to parents and alternative strategies should be considered in future studies. Further studies are needed to evaluate the relationship between intervention dosing on long term motor outcomes.

Dose escalation study of bovine lactoferrin in preterm infants: getting the dose right.

Lactoferrin as a nutritional enteral supplement has emerged as a novel preventative therapy against serious infections in preterm infants, although neonatal studies have demonstrated variable results, in part due to the lack of pharmacokinetic data and differences in the products tested. We conducted a prospective, dose escalation (100, 200, and 300 mg·kg-1·day-1) safety study of bovine lactoferrin (Glanbia Nutritionals, USA) dissolved in sterile water (100 mg·mL-1) for 30 days in preterm infants with birth weight <1500 g. Safety related to adverse events (AEs), tolerability, and exposure-response of lactoferrin was assessed. We enrolled 31 patients [10, 10, and 11 patients, for the lactoferrin treatment groups (100, 200, and 300 mg·kg-1·day-1, respectively)] over a 10-month period. No AEs related to the study solution occurred, and lactoferrin was tolerated by each group. During lactoferrin supplementation, one bloodstream infection occurred in each group, but there were no incidences of urinary tract infections and no cases of necrotizing enterocolitis. Postnatal cytomegalovirus acquisition was detected in the group treated with 200 mg·kg-1·day-1 (n = 2). There were no adverse effects on hepatic, renal, or hematologic function. All of the patients survived to discharge. Bovine lactoferrin at doses up to 300 mg·kg-1·day-1 is safe in preterm infants. Future studies examining higher doses of lactoferrin, length of treatment, and potency of different products will aid in determining the optimal approach for the use of lactoferrin to prevent infections in preterm infants.

The Use of Short-Term Acupressure to Prevent Long-Term PONV: Was This a Case of Too Little, Too Late?

PURPOSE: Postoperative nausea and vomiting (PONV) is a common surgical complication that contributes to poor patient outcomes. The purpose of this study was to determine if acupressure to the P6 pressure point during the immediate postoperative period decreased PONV for the first 24 postoperative hours. DESIGN: This was a double-blind, randomized study. METHODS: Experimental group participants wore a wristband, which administered acupressure to the P6 pressure point of one wrist. Control group wristbands were malpositioned. Bands remained on until patients were discharged from the postanesthesia care unit or up to a maximum of 2 hours. Data on nausea, vomiting, and antiemetic use were tracked for the first 24 postoperative hours. FINDING: There were no statistically significant between-group differences in PONV or antiemetic use. CONCLUSIONS: Short-term postoperative acupressure to one wrist did not lead to a 24-hour decrease in nausea, vomiting, or antiemetic use.

Implementation of a Model-Based Design in a Phase Ib Study of Combined Targeted Agents.

In recent years, investigators have recognized the rigidity of single-agent, safety-only, traditional designs, rendering them ineffective for conducting contemporary early-phase clinical trials, such as those involving combinations and/or biological agents. Novel approaches are required to address these research questions, such as those posed in trials involving targeted therapies. We describe the implementation of a model-based design for identifying an optimal treatment combination, defined by low toxicity and high efficacy, in an early-phase trial evaluating a combination of two oral targeted inhibitors in relapsed/refractory mantle cell lymphoma. Operating characteristics demonstrate the ability of the method to effectively recommend optimal combinations in a high percentage of trials with reasonable sample sizes. The proposed design is a practical, early-phase, adaptive method for use with combined targeted therapies. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of a melanoma helper peptide vaccine plus novel adjuvant combinations. Clin Cancer Res; 23(23); 7158-64. ©2017 AACR.

Combinatorial drug screening and molecular profiling reveal diverse mechanisms of intrinsic and adaptive resistance to BRAF inhibition in V600E BRAF mutant melanomas.

Over half of BRAFV600E melanomas display intrinsic resistance to BRAF inhibitors, in part due to adaptive signaling responses. In this communication we ask whether BRAFV600E melanomas share common adaptive responses to BRAF inhibition that can provide clinically relevant targets for drug combinations. We screened a panel of 12 treatment-naïve BRAFV600E melanoma cell lines with MAP Kinase pathway inhibitors in pairwise combination with 58 signaling inhibitors, assaying for synergistic cytotoxicity. We found enormous diversity in the drug combinations that showed synergy, with no two cell lines having an identical profile. Although the 6 lines most resistant to BRAF inhibition showed synergistic benefit from combination with lapatinib, the signaling mechanisms by which this combination generated synergistic cytotoxicity differed between the cell lines. We conclude that adaptive responses to inhibition of the primary oncogenic driver (BRAFV600E) are determined not only by the primary oncogenic driver but also by diverse secondary genetic and epigenetic changes ("back-seat drivers") and hence optimal drug combinations will be variable. Because upregulation of receptor tyrosine kinases is a major source of drug resistance arising from diverse adaptive responses, we propose that inhibitors of these receptors may have substantial clinical utility in combination with inhibitors of the MAP Kinase pathway.

Impact of supplemental vitamin K1 administration on postoperative blood component requirements after craniosynostosis repair: a prospective, placebo-controlled, randomized, blinded study.

Total cranial vault craniosynostosis repairs often require additional blood transfusions in the intensive care unit. Vitamin K1 participates in hepatic production of procoagulant proteins, and body stores of vitamin K1 are limited and dietary dependent. Surgical stress and diet interference may place infants at risk for vitamin K deficiency. Through design of a surgically stratified, randomized, placebo-controlled, blinded pilot study, we evaluated impact of vitamin K1 supplementation on coagulation parameters in infants after craniosynostosis repair. Patients received intramuscular vitamin K1 or placebo coincident with surgical incision. Serum vitamin K1 levels, protein induced in vitamin K absence-prothrombin, and factor VII were obtained at predetermined intervals after surgery. Patients received blood products in the intensive care unit in accordance with transfusion thresholds. Fifteen patients (vitamin K1 = 6, placebo = 9) completed the study procedures. Despite group assignment, patients received an average of 3 postoperative transfusions. Variations were observed with respect to intraoperative resuscitation of patients between comparably trained pediatric anesthesiologists. Thirty-three percent of patients were vitamin K1 deficient on 1 or more laboratory specimens. All breast-fed patients became deficient. Compared with placebo, elevated serum vitamin K1 levels at 6, 12, and 24 hours in the active drug group (P < 0.0001) were not associated with increased factor VII levels or reduced need for postoperative blood products. However, lack of a standardized intraoperative resuscitation plan may contribute to postoperative coagulopathy and is a major study limitation.

What is the least painful method of anesthetizing a peripheral IV site?

The placement of an intravenous (IV) catheter for the administration of fluids, blood products, and medications is a common intervention for surgical procedures and perianesthesia patients. Although the placement of a peripheral IV may be routine for perianesthesia nurses, it is important to address the patient's level of pain related to the procedure. One technique to diminish the discomfort associated with the IV insertion is anesthetizing the site. The purpose of this study was to compare three methods for anesthetizing peripheral IV catheter sites before insertion to determine which method provides optimal patient comfort during the anesthetizing and IV catheter insertion process. The findings demonstrate that there was no statistical difference in pain when anesthetizing the site using the three methods. However, there was a difference with the IV insertion process. Using 1% lidocaine resulted in the least painful IV insertion.

Effects of lifestyle intervention on health care costs: Improving Control with Activity and Nutrition (ICAN).

OBJECTIVE: To evaluate program and health care costs of a lifestyle intervention in a high-risk obese population. DESIGN: Twelve-month randomized controlled trial comparing lifestyle case management to usual care. SUBJECTS/SETTING: Health plan members (n=147) with obesity (body mass index >/=27) and type 2 diabetes. INTERVENTION: Lifestyle case management entailed individual and group education, support, and referrals by registered dietitians. Those in the usual-care group received educational material. MAIN OUTCOME MEASURES: Medical and pharmaceutical health care costs reimbursed by the participant's primary insurance company. STATISTICAL ANALYSIS: Total costs were modeled using the four-equation model using previous year cost as a predictor. RESULTS: Net cost of the intervention was $328 per person per year. After incorporating program costs, mean health plan costs were $3,586 (95% confidence interval [CI]: -$8,036, -$25, P<0.05) lower in case management compared to usual care. The difference was driven by group differences in medical (-$3,316, 95% CI: -$7,829 to -$320, P<0.05) but not pharmaceutical costs (-$239, 95% CI: -$870 to $280, not statistically significant), with fewer inpatient admissions and costs among case management compared with usual care (admission prevalence: 2.8% vs 22.5% respectively, P<0.001). CONCLUSION: Addition of a modest-cost, registered dietitian-led lifestyle case-management intervention to usual medical care did not increase health care costs and suggested modest cost savings among obese patients with type 2 diabetes. Larger trials are needed to determine whether these results can be replicated in a broader population. The findings can be judiciously applied to support that the addition of a registered dietitian-led lifestyle case-management program to medical care does not increase health care costs.

Temperature dependence of cardiac performance in the lobster Homarus americanus.

The lobster Homarus americanus inhabits ocean waters that vary in temperature over a 25 degrees C range, depending on the season and water depth. To investigate whether the lobster heart functions effectively over a wide range of temperatures we examine the temperature dependence of cardiac performance of isolated lobster hearts in vitro. In addition, we examined whether modulation of the heart by serotonin depends on temperature. The strength of the heartbeat strongly depends on temperature, as isolated hearts are warmed from 2 to 22 degrees C the contraction amplitude decreases by greater than 60%. The rates of contraction and relaxation of the heart are most strongly temperature dependent in the range from 2 to 4 degrees C but become temperature independent at warmer temperatures. Heart rates increase as a function of temperature both in isolated hearts and in intact animals, however hearts in intact animals beat faster in the temperature range of 12-20 degrees C. Interestingly, acute Q10 values for heart rate are similar in vivo and in vitro over most of the temperature range, suggesting that temperature dependence of heart rate arises mainly from the temperature effects on the cardiac ganglion. In contrast to earlier reports suggesting that the strength and the frequency of the lobster heartbeat are positively correlated, we observe no consistent relationship between these parameters as they change as a function of temperature. Stroke volume decreases as a function of temperature. However, the opposing temperature-dependent increase in heart rate partially compensates to produce a relationship between cardiac output and temperature in which cardiac output is maximal at 10 degrees C and significantly decreases above 20 degrees C. Serotonin potentiates contraction amplitude and heart rate in a temperature-independent manner. Overall, our results show that although the parameters underlying cardiac performance show different patterns of temperature dependence, cardiac output remains relatively constant over most of the wide range of environmental temperatures the lobster inhabits in the wild.

Gene profiling and promoter reporter assays: novel tools for comparing the biological effects of botanical extracts on human prostate cancer cells and understanding their mechanisms of action.

The use of botanical mixtures is commonplace in patients with prostate cancer, yet the majority of these products have not been rigorously tested in clinical trials. Here we use PC-SPES, a combination of eight herbs that has been shown to be effective in clinical trials in patients with prostate cancer, as a model system to demonstrate 'proof of principle' as to how gene expression profiling coupled with promoter assays can evaluate the effect of herbal cocktails on human prostate cancer. In addition, we demonstrate how such approaches may be used for standardization of herbal extract activity by comparing the gene profile of PC-SPES with that of PC-CARE, a product with a similar herbal composition. Since prior studies have shown that PC-SPES contains estrogenic organic compounds, and such compounds are known to affect prostate cancer, an important issue is whether these are the primary drivers of the gene profile. Our data suggest that gene expression profiles of LNCaP human prostate cancer cells in response to PC-SPES are different from those found when diethylstilbestrol (DES), a synthetic estrogen, is used, suggesting that the estrogenic moieties within PC-SPES do not drive this expression signature. In contrast, the expression profile of PC-CARE was almost identical to that of DES, highlighting that mixtures containing similar herbal compositions do not necessarily result in similar biological activities. Interestingly, these three agents cause similar in vitro morphological changes and growth effects on LNCaP. To validate the expression profiling data, we evaluated the protein expression and promoter activity of prostate-specific antigen (PSA), a gene induced by PC-SPES but repressed by DES. In order to gain a mechanistic understanding of how PC-SPES and DES affect PSA expression differently, LNCaP cells were transiently transfected with wild-type and mutagenized PSA promoter, ARE concatemers and appropriate controls. We provide evidence that androgen response elements (ARE) II and III within the promoter region are responsible for the suppressive effects of DES and stimulatory effects of PC-SPES. In addition, we show that the effects on PSA transcription are ARE specific in the case of DES while PC-SPES affects this promoter nonspecifically. In conclusion, expression profiling coupled with mechanistic target validation yield valuable clues as to the mode of action of complex botanical mixtures and provides a new way to compare objectively mixtures with similar components either for effect or quality assurance prior to their use in clinical trials.