Scalp Staples Placed in a Pediatric Emergency Department: Feasibility and Benefits of Home Removal.

OBJECTIVES: Scalp lacerations are a common occurrence in the pediatric population. A preferred method of closure in a busy pediatric emergency department (PED) is skin staples, because of their ease of use and rapid application. However, using skin staples also demands that the child have a follow-up visit for their removal. This study examines whether caregivers can be taught how to safely remove their child's skin staples at home, obviating the need for a return clinic visit and its associated costs. METHODS: This is a prospective, convenience study of 30 children older than 4 years presenting with a scalp laceration that the attending physician chose to close with skin staples. Caregivers of enrolled children completed an initial survey and received training in skin staple removal in the PED. Upon discharge, caregivers were given the staple removal device and specific instructions indicating the date for staple removal and how to access an online video reviewing proper staple removal technique. Caregivers were contacted after anticipated staple removal for completion of a follow-up survey. We recorded caregiver success rate at staple removal and measured potential benefits with regard to lost wages, transportation costs, and missed school time. Data were analyzed using descriptive statistics. RESULTS: Twenty-eight (93%) of 30 enrolled caregivers were successful in completely removing their child's staples; one caregiver did not attempt removal and another was lost to follow-up. Twenty-five caregivers (83%) completed follow-up surveys. All caregivers reported that if given a future choice, they would prefer to remove their child's staples at home rather than return to a clinic and all said that they would be "very comfortable" if they needed to remove staples again in the future. Sixty-four percent of caregivers estimated that it would have taken greater than 2 hours to attend a clinic for staple removal. Thirty-two percent of caregivers would have lost greater than US $100 in wages. Eighty-eight percent of children would have missed school time, with 46% having to miss an entire school day. CONCLUSIONS: Caregivers who were taught how to remove their child's scalp staples in the PED before discharge were highly successful at home. Ninety-three percent of enrolled patients had their staples completely removed and no complications were reported. Benefits included avoiding lost wages, lost time attending a follow-up clinic, and lost time from school. Staple removal is a simple technique that can easily be taught to caregivers in a matter of minutes and lead to greater patient and parent satisfaction.

National Maintenance Cost for Precision Diagnostics Under the Verifying Accurate Leading-Edge In Vitro Clinical Test Development (VALID) Act of 2020.

PURPOSE: The proposed legislation Verifying Accurate and Leading-edge In vitro clinical test Development (VALID) clarifies the US Food and Drug Administration's authority to regulate laboratory-developed tests. Many stakeholders have pointed out that the lack of direct US Food and Drug Administration oversight has led to erroneous results that have serious patient consequences-in particular for patients with cancer. Technology Certification is a key provision proposed in VALID to navigate the balance between safety, patient access, and innovation; however, the maintenance cost of the proposed framework after implementation is unclear. METHODS: On the basis of 2019 retrospective data from a laboratory-developed test-based cancer diagnostics laboratory, we expressed laboratory complexity by the number and complexity of assays and in vitro diagnostic technologies. We estimated the national health care cost increase by modeling three stringencies of complying with the Act. We performed sensitivity analysis of our regulatory stringency model taking into account number of patients tested, materials, submission cost, and labor using extra cost per patient as the output. RESULTS: We estimate the national health care cost increase to range from $33M US dollars (USD) to $1,110M USD or $0.21 USD to $0.70 USD per employed person in the United States. Sensitivity analysis demonstrates that regulatory stringency is the primary driver of extra cost per patient. Cancer testing does not reflect all areas of in vitro diagnostics affected by VALID; nonetheless, concrete cost models are paramount in informing the ongoing legislative negotiations. CONCLUSION: Our findings show the critical importance of clarity in the legislative language to ensure balance between VALID's goals of assuring high-quality test performance and the burden to laboratories and overall health care cost.

Cost-effectiveness of combinatorial pharmacogenomic testing for treatment-resistant major depressive disorder patients.

OBJECTIVES: To describe the lifetime outcomes and economic implications of combinatorial pharmacogenomic (CPGx) testing versus treatment as usual (TAU) psychopharmacologic medication selection for a representative major depressive disorder patient who has not responded to previous treatment(s). STUDY DESIGN: Markov state-transition analysis based on clinical studies. METHODS: Clinical validity and utility were based on published findings in prospective clinical studies of a commercially available CPGx test. Data for quality of life, direct costs, and indirect costs were extracted from meta-analyses of published literature on clinical studies and claims databases. Outcomes were assessed from a societal perspective, and included differences between the CPGx and the TAU strategies in quality-adjusted life-years (QALYs), cumulative direct and indirect costs, and cost per QALY gained. RESULTS: CPGx improved the treatment response rate by 70% (1.7 times as high as that with TAU), increasing QALYs by 0.316 years. With these health benefits, CPGx is expected to save $3711 in direct medical costs per patient and $2553 in work productivity costs per patient over the lifetime. The cost-effectiveness of CPGx testing was robust over a wide range of variation in the input parameters, including the scenario when testing efficacy was set to its lower limit. CONCLUSIONS: CPGx testing has been shown by prospective studies to modify treatment decisions for patients nonresponsive to previous treatment(s), with increased rates of treatment response. These effects are projected to increase quality-adjusted survival, and to save both direct and indirect costs to individual patients and society generally.

18F-fluoride PET used for treatment monitoring of systemic cancer therapy: results from the National Oncologic PET Registry.

UNLABELLED: In a national prospective registry, we previously studied the impact of (18)F-sodium fluoride PET (NaF PET) on the intended management of cancer patients with osseous metastases. The clinical impact of NaF PET for monitoring the response to systemic therapies in such patients is unknown. The objective of this study was to assess the impact of NaF PET results obtained for treatment monitoring of systemic cancer therapy. METHODS: Before and after NaF PET, we collected prospective data from referring and interpreting physicians for cancer patients 65 y or older receiving systemic therapy (use of 1 or more categories including hormonal, chemotherapy, bisphosphonates, or immunotherapy). The analysis set consisted of 2,217 patients who underwent 2,839 scans (68% prostate, 17% breast, 6% lung, and 8% other cancers) ordered for treatment monitoring. Two or more categories of systemic therapy were planned in 56% of prostate and 43% of breast cancer patients. RESULTS: The overall rates of prior radionuclide bone imaging were 78%, 76%, and 66% for prostate, breast, and other cancers, respectively. Fifty-seven percent of patients underwent prior NaF PET. Overall change in management associated with NaF PET was 40%. In patients with prior NaF PET scans for comparison, continuing current therapy was planned in 79% when scans showed no change or a decrease or absence of osseous metastasis. Treating physicians planned to switch therapy in 59% of patients after scans showed evidence of new or progressive metastasis. When an additional parameter, estimated prognosis, was worse, switching therapy was even more common (76%). CONCLUSION: The impact of NaF PET used for treatment monitoring was high in patients with evidence of progressive osseous metastasis. Most such patients had plans to switch to a new cancer-directed therapy.

Molecular diagnostics clinical utility strategy: a six-part framework.

The clinical utility of a molecular test rises proportional to a favorable regulatory risk/benefit assessment, and clinical utility is the driver of payer coverage decisions. Although a great deal has been written about clinical utility, debates still center on its 'definition.' We argue that the definition (an impact on clinical outcomes) is self-evident, and improved communications should focus on sequential steps in building and proving an adequate level of confidence for the diagnostic test's clinical value proposition. We propose a six-part framework to facilitate communications between test developers and health technology evaluators, relevant to both regulatory and payer decisions.

Impact of (18)F-Fluoride PET on Intended Management of Patients with Cancers Other Than Prostate Cancer: Results from the National Oncologic PET Registry.

UNLABELLED: The National Oncologic PET Registry prospectively assessed the impact of PET with (18)F-sodium fluoride (NaF PET) on intended management of Medicare patients with suspected or known osseous metastasis. We report our findings for cancers other than prostate and make selected comparisons to our previously reported prostate cancer cohort. METHODS: Data were collected from both referring and interpreting physicians before and after NaF PET in patients (age ≥ 65 y) stratified for initial staging (IS; n = 570), for suspected first osseous metastasis (FOM; n = 1,814; breast, 781 [43%]; lung, 380 [21%]; and all other cancers, 653 [36%]), and for suspected progression of osseous metastasis (POM; n = 435). RESULTS: The dominant indication was bone pain. If NaF PET were unavailable, conventional bone scintigraphy would have been ordered in 85% of patients. In IS, 28% of patients had suspected or confirmed nonosseous metastasis. If neither conventional bone scintigraphy nor NaF PET were available, referring physicians would have ordered other advanced imaging more than 70% of the time rather than initiate treatment for suspected FOM (11%-16%) or POM (18%-22%). When intended management was classified as either treatment or nontreatment, the intended management change for each cancer type was highest in POM, lower in IS, and lowest in FOM. For suspected FOM, intended management change was lower in breast (24%), lung (36%), or other cancers (31%), compared with prostate cancer (44%) (P < 0.0001), but the NaF PET finding (normal/benign/equivocal, probable, or definite metastases) frequencies were similar across cancer types. After normal/benign/equivocal PET results, 15% of breast, 30% lung, and 38% prostate cancer patients had treatment, likely reflecting differences in management of nonosseous disease. For patients with definite metastasis on NaF PET, nonprostate, compared with prostate, cancer patients had post-PET plans for more frequent biopsy, alternative imaging, chemotherapy, and radiotherapy. In the smaller IS and POM cohorts, differences among cancer types were not significant. CONCLUSION: Overall, NaF PET led to change in intended management in a substantial fraction of nonprostate cancer patients. In the setting of suspected FOM, NaF PET had a lower immediate impact on the treat/nontreat decision in nonprostate versus prostate cancer patients, which is consistent with current practice guidelines.

Diabetes technology, innovation, and the U.S. health insurance system.

The flow of funds in the U.S. health care system is crucial both for the provision of services to patients and to encourage innovation that enables long-term improvement of health services. Rising concern about health care costs often includes concerns about inappropriate adoption of costly or unnecessary technology. Many innovations in diabetes technology may involve personal technology, which does not qualify under existing health insurance categories such as "durable medical equipment" or under a currently defined telehealth technology. In such cases, the diabetes technology industry may be developing types of technology that are so innovative they do not have clearly established payment mechanisms in the existing U.S. fee for service health care reimbursement system. This article describes key features of the U.S. health care payment system relevant to developers of new diabetes technologies.

Regulatory and reimbursement innovation.

Coverage with evidence development and parallel review for molecular diagnostics aid regulation and reimbursement.

Impact of 18F-FDG PET used after initial treatment of cancer: comparison of the National Oncologic PET Registry 2006 and 2009 cohorts.

UNLABELLED: Since 2006, the National Oncologic PET Registry has collected prospective data on (18)F-FDG PET performed for cancer indications in Medicare beneficiaries under the coverage-with-evidence-development (CED) policy of the Centers for Medicare & Medicaid Services. In April 2009, coverage for PET performed to inform the initial treatment strategy of most solid tumors was expanded by the Centers for Medicare & Medicaid Services, but they continued to require CED for subsequent treatment strategy evaluations for many cancers. METHODS: For all years, we assessed National Oncologic PET Registry data for bladder, kidney, pancreas, prostate, stomach, small cell lung, uterine, and all other cancers that required CED. We compared clinical profiles and changes in intended management by interval (before or after April 2009, designated as the 2006 and 2009 cohorts) for PET scans performed for restaging or suspected recurrence (2006, n = 30,911; 2009, n = 54,747) or for chemotherapy monitoring (2006, n = 10,234; 2009, n = 15,611). RESULTS: There were slight differences between time periods but little difference by cancer type or patient age within a time period. For restaging or suspected recurrence, comparing the 2006 and 2009 cohorts, total change in intended management for all cancer types was about 33% in those younger than 65 y and about 35% in those older than 65 y (range by cancer type, 31%-41%). The referring physician impression of disease extent (restaging) or prognosis (chemotherapy monitoring) after PET was similar between cohorts. In the 2009 cohort, PET for chemotherapy monitoring was associated with a 25% increase in plans to continue therapy and a complementary decline in plans to adjust therapy. The greatest management impact of PET was during chemotherapy monitoring in the 2009 cohort, where a post-PET prognosis judged to be worse than before PET was associated with a plan to discontinue that therapy in 90% and to change to a different therapy in 65%. CONCLUSION: Our data demonstrate a similar impact of PET on planned management of cancer patients before and after the 2009 expansion of coverage. These results strongly suggest it is unlikely that new useful information will be obtained by extending the coverage of certain cancer types and indications only under CED. Future research on advanced imaging in the management of patients with cancer should focus on optimal sequencing and frequency of PET and other imaging modalities.

Personalized diagnostics: the struggle for position.

For several major cancers, drug selection already pivots on biomarker results (e.g., trastuzumab for breast cancer, and gefitinib and erlotinib for lung cancer). Fast-paced advances in genomic and proteomic laboratory technologies could enable the widespread use of molecular testing before therapy selection in any field of medicine. This article describes two potentially large obstructions to such innovation. First, laboratory tests have traditionally been commodities with low prices, prices that matched the resources required to operate the laboratory technology itself. Assuming that the marginal costs of molecular laboratory technology will fall, there will be a widening chasm between estimated test revenue and the costs of innovative and definitive clinical trials, and regulatory approval for new tests. Without corrective action, even cost-saving laboratory tests could be in shortfall, because they will not be created through upfront investment. Second, it is argued that while diagnostic tests, drugs and surgical procedures should meet a fundamental standard for payer coverage ('will health outcomes be improved?'), molecular diagnostics could require different analysis pathways than those that are used to evaluate interventions.

Development of a novel measure of overcrowding in a pediatric emergency department.

OBJECTIVE: Emergency department (ED) overcrowding has been quantified with a scale that reflects the degree of overcrowding (National ED Overcrowding Scale, or NEDOCS) in general academic EDs. However, validity of the 5-question NEDOCS scale has not been established for a pediatric ED. Our primary objectives were to validate the NEDOCS model in our institution's pediatric ED and explore the possibility of another pediatric ED overcrowding model that would be better than the NEDOCS model. METHODS: Objective data were determined by prospectively collecting 20 variables at 42 random site-sampling times in one pediatric ED. Data were obtained by counting patients, determining patient's times, and obtaining information from registration, triage, and ancillary services. The 5 questions needed for the NEDOCS scale were among the data collected. Expert consensus (EC) was obtained using a Likert scale completed by the charge nurse and ED physicians who rated the degree of overcrowding. National ED Overcrowding Scale scores were compared with EC score to determine predictive validity of a model for a pediatric ED. Spearman correlation and multivariable linear regression were used to evaluate individual variables. RESULTS: Overcrowding based on EC score was found in 18 (44%) of 41 times in the pediatric ED. In pediatric EDs, high correlations were found between EC score and NEDOCS (0.68), number of patients in the waiting room (0.74), full rooms (0.64), and total registered patients (0.65). In a multivariable analysis, a combination of patients in the waiting room and total registered patients had a high correlation (0.80) with EC score in the pediatric ED. CONCLUSIONS: Overcrowding is quantifiable in a pediatric ED. Although the NEDOCS performed well in the pediatric ED, it was outperformed by other variables and other variable combinations. In this pediatric ED, a combination of 2 variables, total registered patients and patients in the waiting room, was a better model than the NEDOCS score for quantifying pediatric ED overcrowding.

The endocytotic pathway is required for increased A beta 42 secretion during apoptosis.

Secretion and progressive cerebral accumulation of beta-amyloid peptides (A beta), which derive by endoproteolytic ('amyloidogenic') processing of beta-amyloid precursor protein (APP), are felt to represent collectively an early and necessary event in the pathogenesis of Alzheimer's disease. APP amyloidogenic processing can occur via secretory or endocytotic pathways, but the relative contribution of these pathways to A beta secretion remains to be established. The effect of apoptosis on amyloidogenic processing and A beta secretion similarly is incompletely understood. We tested the hypothesis that APP processing by the endocytotic pathway represents a stress-related neural cell response, by comparing A beta secretion after induction of apoptosis in PC12 cells transfected either for endocytosis-competent or -deficient APP. Newly prepared adenoviral vectors encompassing targeted mutagenesis of the cytoplasmic tail YENP tetrapeptide sequence, which serves as the principal APP internalization signal, were used to express endocytosis-deficient holoprotein. We report that the endocytotic pathway is required for the generation and secretion of A beta 42, and that secretion of this neurotoxic peptide increases significantly during apoptosis. We demonstrate additionally that more A beta 40 apparently is generated in secretory compartments during apoptosis when APP processing by the endocytotic pathway is impaired.

Conformational changes and truncation of tau protein during tangle evolution in Alzheimer's disease.

The conformation-dependent antibodies Tau-66 and Alz-50 recognize discontinuous epitopes on the tau molecule (residues 155-244 & 305-314 and 5-15 & 312-322, respectively), thereby defining two distinct conformations. In double- and triple-label immunofluorescence experiments we discovered that specific populations of neurofibrillary tangles display either the Alz-50 or the Tau-66 conformation, but not both. In combination with other antibodies to several domains of the molecule we demonstrate that the conformation recognized by Alz-50 seems to be an early event in the formation of neurofibrillary tangles. This conformation is characterized by the presence of predominantly intact N- and C- termini. By contrast, the Tau-66 conformation is likely a later event in tangle development, being favored in structures containing truncations of both the N- and C- termini. We propose a sequence of events that occurs during the formation and evolution of neurofibrillary tangles based on the initial conformation adopted by tau. In this scheme, the Tau-66 conformation in neurofibrillary tangles may arise from amino and carboxy truncation of tau after it has assumed the Alz-50 conformation. These results indicate that tau structure within the NFT is dynamic in that tau can undergo a "refolding" event following N- and C-terminal truncation.

Widely spread butyrylcholinesterase can hydrolyze acetylcholine in the normal and Alzheimer brain.

BACKGROUND: Butyrylcholinesterase (BChE), also known as the "pseudo" or "non-neuronal" cholinesterase, is traditionally thought to have a restricted CNS distribution and to play little, if any, role in cholinergic transmission. OBJECTIVE: To reanalyze the role of BChE in the human brain with more sensitive methodology. METHODS: Three brains were examined with acetylcholinesterase and BChE histochemistry. The sections were examined with bright- and dark-field microscopy. RESULTS: The histochemical parameters used in the present experiments showed that BChE activity was present in all hippocampal and temporal neocortical areas known to receive cholinergic input. At all of these locations, the BChE enzyme could hydrolyze the acetylcholine surrogate acetylthiocholine. A substantial portion of the hippocampal and neocortical BChE appeared to be located within neuroglia and their processes. CONCLUSIONS: Butyrylcholinesterase may have a greater role in cholinergic transmission than previously surmised, making BChE inhibition an important therapeutic goal in Alzheimer's disease. The results also suggest that the role of neuroglia in cholinergic transmission may be analogous to their well known role in glutamatergic transmission.