ABSTRACT
The delivery of cancer care has never changed as rapidly and dramatically as we have seen with the coronavirus disease 2019 (COVID-19) pandemic. During the early phase of the pandemic, recommendations for the management of oncology patients issued by various professional societies and government agencies did not recognize the significant regional differences in the impact of the pandemic. California initially experienced lower than expected numbers of cases, and the health care system did not experience the same degree of the burden that had been the case in other parts of the country. In light of promising trends in COVID-19 infections and mortality in California, by late April 2020, discussions were initiated for a phased recovery of full-scale cancer services. However, by July 2020, a surge of cases was reported across the nation, including in California. In this review, the authors share the response and recovery planning experience of the University of California (UC) Cancer Consortium in an effort to provide guidance to oncology practices. The UC Cancer Consortium was established in 2017 to bring together 5 UC Comprehensive Cancer Centers: UC Davis Comprehensive Cancer Center, UC Los Angeles Jonsson Comprehensive Cancer Center, UC Irvine Chao Family Comprehensive Cancer Center, UC San Diego Moores Cancer Center, and the UC San Francisco Helen Diller Family Comprehensive Cancer Center. The interventions implemented in each of these cancer centers are highlighted, with a focus on opportunities for a redesign in care delivery models. The authors propose that their experiences gained during this pandemic will enhance pre-pandemic cancer care delivery.
Subject(s)
COVID-19 , Cancer Care Facilities/organization & administration , Delivery of Health Care/organization & administration , Neoplasms/therapy , COVID-19/complications , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Testing , California/epidemiology , Global Health , Humans , Infection Control/methods , Infection Control/organization & administration , Neoplasms/complications , Neoplasms/diagnosis , Pandemics , Telemedicine/methods , Telemedicine/organization & administrationABSTRACT
The analysis of cell-free DNA (cfDNA) from plasma offers great promise for the earlier detection of cancer. At present, changes in DNA sequence, methylation, or copy number are the most sensitive ways to detect the presence of cancer. To further increase the sensitivity of such assays with limited amounts of sample, it would be useful to be able to evaluate the same template molecules for all these changes. Here, we report an approach, called MethylSaferSeqS, that achieves this goal, and can be applied to any standard library preparation method suitable for massively parallel sequencing. The innovative step was to copy both strands of each DNA-barcoded molecule with a primer that allows the subsequent separation of the original strands (retaining their 5-methylcytosine residues) from the copied strands (in which the 5-methylcytosine residues are replaced with unmodified cytosine residues). The epigenetic and genetic alterations present in the DNA molecules can then be obtained from the original and copied strands, respectively. We applied this approach to plasma from 265 individuals, including 198 with cancers of the pancreas, ovary, lung, and colon, and found the expected patterns of mutations, copy number alterations, and methylation. Furthermore, we could determine which original template DNA molecules were methylated and/or mutated. MethylSaferSeqS should be useful for addressing a variety of questions relating genetics and epigenetics.
Subject(s)
DNA Copy Number Variations , Neoplasms , Female , Humans , Methylation , 5-Methylcytosine , DNA/genetics , Mutation , Neoplasms/genetics , DNA MethylationABSTRACT
BACKGROUND: The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood. METHODS: We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use. RESULTS: Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 [noninferiority margin, -8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not. CONCLUSIONS: A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).
Subject(s)
Antineoplastic Agents , Chemotherapy, Adjuvant , Circulating Tumor DNA , Colonic Neoplasms , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Australia , Chemotherapy, Adjuvant/methods , Circulating Tumor DNA/analysis , Circulating Tumor DNA/blood , Colonic Neoplasms/blood , Colonic Neoplasms/mortality , Colonic Neoplasms/pathology , Colonic Neoplasms/therapy , Disease-Free Survival , Fluorouracil/therapeutic use , Humans , Neoplasm Recurrence, Local/prevention & control , Neoplasm Staging , Oxaliplatin/therapeutic useABSTRACT
OBJECTIVES: Health technology assessment (HTA) guidance often recommends a 3% real annual discount rate, the appropriateness of which has received limited attention. This article seeks to identify an appropriate rate for high-income countries because it can influence projected cost-effectiveness and hence resource allocation recommendations. METHODS: The author conducted 2 Pubmed.gov searches. The first sought articles on the theory for selecting a rate. The second sought HTA guidance documents. RESULTS: The first search yielded 21 articles describing 2 approaches. The "Ramsey Equation" sums contributions by 4 factors: pure time preference, catastrophic risk, wealth effect, and macroeconomic risk. The first 3 factors increase the discount rate because they indicate future impacts are less important, whereas the last, suggesting greater future need, decreases the discount rate. A fifth factor-project-specific risk-increases the discount rate but does not appear in the Ramsey Equation. Market interest rates represent a second approach for identifying a discount rate because they represent competing investment returns and hence opportunity costs. The second search identified HTA guidelines for 32 high-income countries. Twenty-two provide no explicit rationale for their recommended rates, 8 appeal to market interest rates, 3 to consistency, and 3 to Ramsey Equation factors. CONCLUSIONS: Declining consumption growth and real interest rates imply HTA guidance should reduce recommended discount rates to 1.5 to 2+%. This change will improve projected cost-effectiveness for therapies with long-term benefits and increase the impact of accounting for long-term drug price dynamics, including reduced prices attending loss of market exclusivity.
Subject(s)
Cost-Benefit Analysis , Technology Assessment, Biomedical , Technology Assessment, Biomedical/economics , Humans , Developed Countries/economics , Resource Allocation/economicsABSTRACT
PURPOSE OF REVIEW: Enhanced recovery after thoracic surgery (ERATS) has continued its growth in popularity over the past few years, and evidence for its utility is catching up to other specialties. This review will present and examine some of that accumulated evidence since guidelines sponsored by the Enhanced Recovery after Surgery (ERAS) Society and the European Society of Thoracic Surgeons (ESTS) were first published in 2019. RECENT FINDINGS: The ERAS/ESTS guidelines published in 2019 have not been updated, but new studies have been done and new data has been published regarding some of the individual components of the guidelines as they relate to thoracic and lung resection surgery. While there is still not a consensus on many of these issues, the volume of available evidence is becoming more robust, some of which will be incorporated into this review. SUMMARY: The continued accumulation of data and evidence for the benefits of enhanced recovery techniques in thoracic and lung resection surgery will provide the thoracic anesthesiologist with guidance on how to best care for these patients before, during, and after surgery. The data from these studies will also help to elucidate which components of ERAS protocols are the most beneficial, and which components perhaps do not provide as much benefit as previously thought.
Subject(s)
Enhanced Recovery After Surgery , Pulmonary Surgical Procedures , Thoracic Surgery , Humans , Perioperative Care/methods , Societies, MedicalABSTRACT
Aging is associated with neuromuscular system changes that may have implications for the recruitment and firing behaviors of motor units (MUs). In previous studies, we observed that young adults recruit subpopulations of triceps surae MUs during tasks that involved leaning in five directions: common units that were active during different leaning directions and unique units that were active in only one leaning direction. Furthermore, the MU subpopulation firing behaviors [average firing rate (AFR), coefficient of variation (CoVISI), and intermittent firing] modulated with leaning direction. The purpose of this study was to examine whether older adults exhibited this regional recruitment of MUs and firing behaviors. Seventeen older adults (aged 74.8 ± 5.3 yr) stood on a force platform and maintained their center of pressure leaning in five directions. High-density surface electromyography recordings from the triceps surae were decomposed into single MU action potentials. A MU tracking analysis identified groups of MUs as being common or unique across the leaning directions. Although leaning in different directions did not affect the AFR and CoVISI of common units (P > 0.05), the unique units responded to the leaning directions by increasing AFR and CoVISI, albeit modestly (F = 18.51, P < 0.001). The unique units increased their intermittency with forward leaning (F = 9.22, P = 0.003). The mediolateral barycenter positions of MU activity in both subpopulations were found in similar locations for all leaning directions (P > 0.05). These neuromuscular changes may contribute to the reduced balance performance seen in older adults.NEW & NOTEWORTHY In this study, we observed differences in motor unit recruitment and firing behaviors of distinct subpopulations of motor units in the older adult triceps surae muscle from those observed in the young adult. Our results suggest that the older adult central nervous system may partially lose the ability to regionally recruit and differentially control motor units. This finding may be an underlying cause of balance difficulties in older adults during directionally challenging leaning tasks.
Subject(s)
Muscle Contraction , Muscle, Skeletal , Young Adult , Humans , Aged , Muscle Contraction/physiology , Muscle, Skeletal/physiology , Electromyography , Leg , Postural Balance , Recruitment, Neurophysiological/physiology , Isometric ContractionABSTRACT
It has been shown that when humans lean in various directions, the central nervous system (CNS) recruits different motoneuron pools for task completion; common units that are active during different leaning directions, and unique units that are active in only one leaning direction. We used high-density surface electromyography (HD-sEMG) to examine if motor unit (MU) firing behavior was dependent on leaning direction, muscle (medial and lateral gastrocnemius; soleus), limits of stability, or whether a MU is considered common or unique. Fourteen healthy participants stood on a force platform and maintained their center of pressure in five different leaning directions. HD-sEMG recordings were decomposed into MU action potentials and the average firing rate (AFR), coefficient of variation (CoVISI), and firing intermittency were calculated on the MU spike trains. During the 30°-90° leaning directions both unique units and common units had higher firing rates (F = 31.31, P < 0.0001). However, the unique units achieved higher firing rates compared with the common units (mean estimate difference = 3.48 Hz, P < 0.0001). The CoVISI increased across directions for the unique units but not for the common units (F = 23.65, P < 0.0001). Finally, intermittent activation of MUs was dependent on the leaning direction (F = 11.15, P < 0.0001), with less intermittent activity occurring during diagonal and forward-leaning directions. These results provide evidence that the CNS can preferentially control separate motoneuron pools within the ankle plantarflexors during voluntary leaning tasks for the maintenance of standing balance.NEW & NOTEWORTHY In this study, we demonstrate that the different subpopulations of motor units within the three muscles comprising the ankle plantarflexors behave differently during multidirectional leaning. Our results suggest that the central nervous system has the capability to control distinct subpopulations of motor units to meet the force requirements necessary for leaning. This may allow for a precise, efficient, and flexible control strategy for the maintenance of standing balance.
Subject(s)
Muscle Contraction , Muscle, Skeletal , Humans , Muscle Contraction/physiology , Muscle, Skeletal/physiology , Motor Neurons/physiology , Leg , ElectromyographyABSTRACT
OBJECTIVE: We aimed to identify social needs of gynecologic oncology patients using a self-administered social needs assessment tool (SNAT), compare the SNAT to a formal social work assessment performed by cancer care navigators (CCN), and provide SNAT-informed community resources. METHODS: We analyzed prospectively collected data from a performance improvement initiative in a safety-net gynecologic oncology clinic between October 2021 and July 2022. We screened for eight social needs domains, health literacy, desire for social work, and presence of urgent needs. Clinicodemographic data were abstracted from the electronic medical record. Univariate descriptive statistics were used. Inter-rater reliability for social needs domains was assessed using percent agreement. RESULTS: 1010 unique patients were seen over this study period. 488 (48%) patients completed the SNAT, of which 265 (54%) screened positive for ≥1 social need. 83 (31%) patients were actively receiving cancer treatment, 140 (53%) were in post-treatment surveillance, and 42 (16%) had benign gynecologic diagnoses. Transportation (19% vs 25%), housing insecurity (18% vs 19%), and desire to speak with a social worker (16% vs 27%) were the 3 most common needs in both the entire cohort and among patients actively receiving cancer treatment. 78% patients in active treatment were seen by a CCN and received SNAT informed community resources. The percent agreement between the SNAT and formal CCN assessment ranged from 72%-94%. CONCLUSIONS: The self-administered SNAT identified many unmet social needs among gynecologic oncology patients, corresponded well with the formal social work CCN assessment, and informed the provision of community resources.
Subject(s)
Genital Neoplasms, Female , Health Literacy , Humans , Female , Genital Neoplasms, Female/therapy , Reproducibility of Results , Social SupportABSTRACT
OBJECTIVES: Guidance on the conduct of health technology assessments rarely recommends accounting for anticipated future price declines that can follow loss of marketing exclusivity. This article explores when it is appropriate to account for generic pricing and whether it can influence cost-effectiveness estimates. METHODS: This article presents 4 case studies. Case study 1 considers a hypothetical drug used by a first patient cohort at branded prices and by subsequent, "downstream" cohorts at generic prices. Case study 2 explores whether statin assessments should account for generic prices for downstream cohorts that gain access after the initial cohort. Case study 3 uses a simplified spreadsheet model to assess the impact of accounting for generic pricing for inclisiran, used when statins insufficiently reduce cholesterol. Case study 4 amends this model for a hypothetical, advanced, follow-on treatment displacing inclisiran. RESULTS: Assessments should include generic pricing even if the first cohort using a drug pays branded prices and only downstream cohorts pay generic prices (case study 1). Because eventual generic pricing for statins did not depend on decisions for downstream cohorts, assessing reimbursement for those cohorts could safely omit generic pricing (case study 2). For inclisiran (case study 3), including generic pricing notably improved estimated cost-effectiveness. Displacing inclisiran with an advanced therapy (case study 4) modestly affected estimated cost-effectiveness. CONCLUSIONS: Although this analysis relies on simplified and hypothetical models, it demonstrates that accounting for generic pricing might substantially reduce estimated cost-effectiveness ratios. Doing so when warranted is crucial to improving health technology assessment validity.
Subject(s)
Drug Costs , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Humans , Drugs, Generic , Cost-Benefit AnalysisABSTRACT
OBJECTIVE: To describe differences in clinical and demographic characteristics between patients with episodic migraine (EM) or chronic migraine (CM) and determine the effect of migraine subtype on patient-reported outcome measures (PROM). BACKGROUND: Prior studies have characterized migraine in the general population. While this provides a basis for our understanding of migraine, we have less insight into the characteristics, comorbidities, and outcomes of migraine patients who present to subspecialty headache clinics. These patients represent a subset of the population that bears the greatest burden of migraine disability and are more representative of migraine patients who seek medical care. Valuable insights can be gained from a better understanding of CM and EM in this population. METHODS: We conducted a retrospective observational cohort study of patients with CM or EM seen in the Cleveland Clinic Headache Center between January 2012 and June 2017. Demographics, clinical characteristics, and patient-reported outcome measures (3-Level European Quality of Life 5-Dimension [EQ-5D-3L], Headache Impact Test-6 [HIT-6], Patient Health Questionnaire-9 [PHQ-9]) were compared between groups. RESULTS: Eleven thousand thirty-seven patients who had 29,032 visits were included. More CM patients reported being on disability 517/3652 (14.2%) than EM patients 249/4881 (5.1%) and had significantly worse mean HIT-6 (67.3 ± 7.4 vs. 63.1 ± 7.4, p < 0.001) and median [interquartile range] EQ-5D-3L (0.77 [0.44-0.82] vs. 0.83 [0.77-1.00], p < 0.001), and PHQ-9 (10 [6-16] vs. 5 [2-10], p < 0.001). CONCLUSIONS: There are multiple differences in demographic characteristics and comorbid conditions between patients with CM and EM. After adjustment for these factors, CM patients had higher PHQ-9 scores, lower quality of life scores, greater disability, and greater work restrictions/unemployment.
Subject(s)
Migraine Disorders , Quality of Life , Humans , Retrospective Studies , Migraine Disorders/epidemiology , Migraine Disorders/therapy , Headache , Patient Reported Outcome Measures , Chronic DiseaseABSTRACT
PURPOSE OF REVIEW: To summarize the most recent publications highlighting the trends and disparities among patients diagnosed with high-risk endometrial cancer. RECENT FINDINGS: Endometrial cancer mortality continues to rise, driven by the increasing incidence of high-risk histologic subtypes that accounts for a disproportionate number of endometrial cancer deaths. The lack of progress made in endometrial cancer treatment, particularly of high-risk histologic subtypes, disproportionately affects black women who are more likely to be diagnosed with these aggressive tumor types. Even when accounting for high-risk histology, various factors across the spectrum of care may influence the survival disparities between black and white women, including timely access to guideline-concordant care, clinical trial enrollment, and systemic racism that impacts cancer outcomes. SUMMARY: In this review, we highlight the disproportionate impact of worsening endometrial cancer mortality and healthcare inequalities contributing to the endometrial cancer survival disparity between black and white women.
Subject(s)
Endometrial Neoplasms , Healthcare Disparities , Female , Humans , Black or African American , Endometrial Neoplasms/therapy , Endometrial Neoplasms/diagnosis , Neoplasm Staging , WhiteABSTRACT
While many of the maladies of the 20th century are steadily coming under control, the march of neurodegenerative disorders continues largely unchecked. Dementias are an exemplar of such disorders; their incidence and prevalence continue to rise, in large part due to a steadily ageing population worldwide. They represent a group of chronic, progressive and, ultimately, fatal neurodegenerative diseases. Dementia has remained therapeutically recalcitrant. It is not a single disease, and because of that, we cannot expect a single panacea. While primary prevention rightly gains prominence, those with established disease currently require a shift in focus from curative intent towards improved quality of life. Enter palliative care. The sheer number and complexity of needs of patients with dementia, from the physical to the psychosocial and spiritual, necessitates the engagement of a wide range of medical disciplines, nursing and allied health professionals. One of those disciplines, as highlighted in the recent Australian Royal Commission into Aged Care Quality and Safety, is palliative care. This paper shall expand upon that role in the overall context of care for those with dementia.
Subject(s)
Dementia , Palliative Care , Humans , Aged , Dementia/psychology , Quality of Life , Australia , AgingABSTRACT
OBJECTIVES: Health technology assessment (HTA) organizations vary in terms of how they conduct assessments. We assess whether and to what extent HTA bodies have adopted societal and novel elements of value in their economic evaluations. METHODS: After categorizing "societal" and "novel" elements of value, we reviewed fifty-three HTA guidelines. We collected data on whether each guideline mentioned each societal or novel element of value, and if so, whether the guideline recommended the element's inclusion in the base case, sensitivity analysis, or qualitative discussion in the HTA. RESULTS: The HTA guidelines mention on average 5.9 of the twenty-one societal and novel value elements we identified (range 0-16), including 2.3 of the ten societal elements and 3.3 of the eleven novel value elements. Only four value elements (productivity, family spillover, equity, and transportation) appear in over half of the HTA guidelines, whereas thirteen value elements are mentioned in fewer than one-sixth of the guidelines, and two elements receive no mention. Most guidelines do not recommend value element inclusion in the base case, sensitivity analysis, or qualitative discussion in the HTA. CONCLUSIONS: Ideally, more HTA organizations will adopt guidelines for measuring societal and novel value elements, including analytic considerations. Importantly, simply recommending in guidelines that HTA bodies consider novel elements may not lead to their incorporation into assessments or ultimate decision making.
Subject(s)
Technology Assessment, Biomedical , Cost-Benefit AnalysisABSTRACT
We report a sensitive PCR-based assay called Repetitive Element AneupLoidy Sequencing System (RealSeqS) that can detect aneuploidy in samples containing as little as 3 pg of DNA. Using a single primer pair, we amplified â¼350,000 amplicons distributed throughout the genome. Aneuploidy was detected in 49% of liquid biopsies from a total of 883 nonmetastatic, clinically detected cancers of the colorectum, esophagus, liver, lung, ovary, pancreas, breast, or stomach. Combining aneuploidy with somatic mutation detection and eight standard protein biomarkers yielded a median sensitivity of 80% in these eight cancer types, while only 1% of 812 healthy controls scored positive.
Subject(s)
Aneuploidy , Neoplasms , Repetitive Sequences, Nucleic Acid , Biomarkers, Tumor , Circulating Tumor DNA , DNA/genetics , Esophagus , Humans , Liquid Biopsy , Mutation , Neoplasms/diagnosis , Neoplasms/genetics , Repetitive Sequences, Nucleic Acid/genetics , Whole Genome SequencingABSTRACT
We used data from the US Cancer Statistics database to determine trends in cancer incidence, stratified by age, race, and ethnicity, among women aged 20 years or older during an 18-year study period (2001-2018). We limited analysis to cancers associated with 5 modifiable risk factors: tobacco use, excess body fat, alcohol consumption, insufficient physical activity, and human papillomavirus infection. The incidence of cancers associated with obesity have risen, particularly among women aged 20 to 49 years (vs ≥50 y) and among Hispanic women. Strategies that address obesity rates in these populations may help decrease cancer risk.
Subject(s)
Neoplasms , Humans , Female , United States/epidemiology , Young Adult , Adult , Incidence , Neoplasms/epidemiology , Neoplasms/etiology , Risk Factors , Obesity/complications , Obesity/epidemiology , EthnicityABSTRACT
BACKGROUND: We examined racial and ethnic differences in medication use for a representative US population of patients with Alzheimer's disease and related dementias (ADRD). METHODS: We examined cholinesterase inhibitors and memantine initiation, non-adherence, and discontinuation by race and ethnicity, using data from the 2000-2016 Health and Retirement Study linked with Medicare and Medicaid claims. RESULTS: Among newly diagnosed ADRD patients (n = 1299), 26% filled an ADRD prescription ≤90 days and 36% ≤365 days after diagnosis. Among individuals initiating ADRD-targeted treatment (n = 1343), 44% were non-adherent and 24% discontinued the medication during the year after treatment initiation. Non-Hispanic Blacks were more likely than Whites to not adhere to ADRD medication therapy (odds ratio: 1.50 [95% confidence interval: 1.07-2.09]). DISCUSSION: Initiation of ADRD-targeted medications did not vary by ethnoracial group, but non-Hispanic Blacks had lower adherence than Whites. ADRD medication non-adherence and discontinuation were substantial and may relate to cost and access to care. HIGHLIGHTS: Initiation of anti-dementia medications among newly diagnosed Alzheimer's disease and related dementias (ADRD) patients was low in all ethnoracial groups. ADRD medication non-adherence and discontinuation were substantial and may relate to cost and access to care. Compared to Whites, Blacks and Hispanics had lower use, poorer treatment adherence, and more frequent discontinuation of ADRD medication, but when controlling for disease severity and socioeconomic factors, racial disparities diminish. Our findings demonstrate the importance of adjusting for socioeconomic characteristics and disease severity when studying medication use and adherence in ADRD patients.
Subject(s)
Alzheimer Disease , Ethnicity , Humans , Aged , United States , Alzheimer Disease/epidemiology , Medicare , Retrospective Studies , WhiteABSTRACT
Animal models provide important tools to study biological and environmental factors that shape brain function and behavior. These models can be effectively leveraged by drawing on concepts from the National Institute of Mental Health Research Domain Criteria (RDoC) Initiative, which aims to delineate molecular pathways and neural circuits that underpin behavioral anomalies that transcend psychiatric conditions. To study factors that contribute to individual differences in emotionality and stress reactivity, our laboratory utilized Sprague-Dawley rats that were selectively bred for differences in novelty exploration. Selective breeding for low versus high locomotor response to novelty produced rat lines that differ in behavioral domains relevant to anxiety and depression, particularly the RDoC Negative Valence domains, including acute threat, potential threat, and loss. Bred Low Novelty Responder (LR) rats, relative to their High Responder (HR) counterparts, display high levels of behavioral inhibition, conditioned and unconditioned fear, avoidance, passive stress coping, anhedonia, and psychomotor retardation. The HR/LR traits are heritable, emerge in the first weeks of life, and appear to be driven by alterations in the developing amygdala and hippocampus. Epigenomic and transcriptomic profiling in the developing and adult HR/LR brain suggest that DNA methylation and microRNAs, as well as differences in monoaminergic transmission (dopamine and serotonin in particular), contribute to their distinct behavioral phenotypes. This work exemplifies ways that animal models such as the HR/LR rats can be effectively used to study neural and molecular factors driving emotional behavior, which may pave the way toward improved understanding the neurobiological mechanisms involved in emotional disorders.
Subject(s)
Anxiety , Depression , Animals , Anxiety/metabolism , Anxiety Disorders , Depression/genetics , Depression/metabolism , Disease Models, Animal , Rats , Rats, Sprague-DawleyABSTRACT
Acute kidney injury (AKI) is a complication associated with vancomycin. Previous studies demonstrated that the combination of vancomycin and piperacillin-tazobactam increases the risk of AKI compared to vancomycin with meropenem or cefepime. These studies did not utilize area under the curve (AUC)-based dosing, which reduces vancomycin exposure and may decrease nephrotoxicity compared with trough-based dosing. This study evaluated the incidence of AKI in patients receiving AUC-dosed vancomycin with either concomitant piperacillin-tazobactam (VPT) or meropenem or cefepime (VMC). This retrospective cohort study included patients admitted to Sentara Norfolk General Hospital between October 2019 and September 2020 who received AUC-dosed vancomycin and concomitant piperacillin-tazobactam, meropenem, or cefepime for at least 48 h. The primary outcome was the incidence of AKI during treatment or within 24 h of discontinuation. A total of 435 patients (VPT, n = 331; VMC, n = 104) who received a median duration of 4 days of treatment were included. The incidence of AKI was significantly higher with VPT than with VMC (13.6% versus 4.8% [P = 0.014]). Multivariable analysis showed VPT to be an independent risk factor for the development of AKI (odds ratio [OR], 3.00 [95% confidence interval {CI}, 1.15 to 7.76]). VPT was associated with more frequent AKI than VMC, even with the relatively short courses of antimicrobial therapy administered in this population. In comparison with the precedent in the literature for trough-based vancomycin dosing, our results suggest that the use of AUC-based vancomycin dosing in combination with piperacillin-tazobactam, meropenem, or cefepime may result in a lower overall incidence of AKI.
Subject(s)
Acute Kidney Injury , Vancomycin , Acute Kidney Injury/chemically induced , Acute Kidney Injury/epidemiology , Anti-Bacterial Agents/adverse effects , Cefepime/adverse effects , Drug Therapy, Combination , Humans , Incidence , Meropenem/adverse effects , Piperacillin/adverse effects , Piperacillin, Tazobactam Drug Combination/adverse effects , Retrospective Studies , Vancomycin/adverse effectsABSTRACT
PURPOSE: This study aimed to estimate the cost-effectiveness of exome sequencing (ES) and genome sequencing (GS) for children. METHODS: We modeled costs, diagnoses, and quality-adjusted life years (QALYs) for diagnostic strategies for critically ill infants (aged <1 year) and children (aged <18 years) with suspected genetic conditions: (1) standard of care (SOC) testing, (2) ES, (3) GS, (4) SOC followed by ES, (5) SOC followed by GS, (6) ES followed by GS, and (7) SOC followed by ES followed by GS. We calculated the 10-year incremental cost per additional diagnosis, and lifetime incremental cost per QALY gained, from a health care perspective. RESULTS: First-line GS costs $15,048 per diagnosis vs SOC for infants and $27,349 per diagnosis for children. If GS is unavailable, ES represents the next most efficient option compared with SOC ($15,543 per diagnosis for infants and $28,822 per diagnosis for children). Other strategies provided the same or fewer diagnoses at a higher incremental cost per diagnosis. Lifetime results depend on the patient's assumed long-term prognosis after diagnosis. For infants, GS ranged from cost-saving (vs all alternatives) to $18,877 per QALY (vs SOC). For children, GS (vs SOC) ranged from $119,705 to $490,047 per QALY. CONCLUSION: First-line GS may be the most cost-effective strategy for diagnosing infants with suspected genetic conditions. For all children, GS may be cost-effective under certain assumptions. ES is nearly as efficient as GS and hence is a viable option when GS is unavailable.
Subject(s)
Exome , Child , Chromosome Mapping , Cost-Benefit Analysis , Exome/genetics , Humans , Infant , Quality-Adjusted Life Years , Exome Sequencing/methodsABSTRACT
BACKGROUND: Coformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS). OBJECTIVE: Determine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial. METHODS: Adults with El Escorial Definite ALS ≤18 months from symptom onset were randomised to PB/ TURSO or placebo for 6 months. Those completing randomised treatment could enrol in an open-label extension (OLE) phase and receive PB/TURSO for ≤30 months. Times to the following individual or combined key events were compared in the originally randomised treatment groups over a period spanning trial start through July 2020 (longest postrandomisation follow-up, 35 months): death, tracheostomy, permanent assisted ventilation (PAV) and first hospitalisation. RESULTS: Risk of any key event was 47% lower in those originally randomised to PB/TURSO (n=87) versus placebo (n=48, 71% of whom received delayed-start PB/TURSO in the OLE phase) (HR=0.53; 95% CI 0.35 to 0.81; p=0.003). Risks of death or tracheostomy/PAV (HR=0.51; 95% CI 0.32 to 0.84; p=0.007) and first hospitalisation (HR=0.56; 95% CI 0.34 to 0.95; p=0.03) were also decreased in those originally randomised to PB/TURSO. CONCLUSIONS: Early PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS. TRIAL REGISTRATION NUMBER: NCT03127514; NCT03488524.