Health and longevity in all organisms are strongly influenced by the environment. To fully understand how environmental factors interact with genetic and stochastic factors to modulate the aging process, it is crucial to precisely control environmental conditions for long-term studies. In the commonly used model organism Caenorhabditis elegans, existing assays for healthspan and lifespan have inherent limitations, making it difficult to perform large-scale longitudinal aging studies under precise environmental control. To address these constraints, we developed the Health and Lifespan Testing Hub (HeALTH), an automated, microfluidic-based system for robust longitudinal behavioral monitoring. Our system provides long-term (i.e. entire lifespan) spatiotemporal environmental control. We demonstrate healthspan and lifespan studies under a variety of genetic and environmental perturbations while observing how individuality plays a role in the aging process. This system is generalizable beyond aging research, particularly for short- or long-term behavioral assays, and could be adapted for other model systems.
BACKGROUND: Rituximab is a top-selling biologic that was first approved by the FDA in 1997 for a non-Hodgkin lymphoma orphan indication. It has since been approved for additional orphan indications, with rheumatoid arthritis as the only FDA-approved, nonorphan indication. Evidence suggests that rituximab is frequently used off-label, but information on its use over time and indications for use in the United States is limited. OBJECTIVE: To assess incident rituximab use over time in an integrated health care delivery system. METHODS: This was a cross-sectional, retrospective study. Data were collected from administrative databases and manual chart reviews. Patients who received their first rituximab infusion between October 1, 2009, and December 31, 2017, and who were not a part of a clinical trial were included. Indication for use (FDA-approved orphan/nonorphan, off-label) was determined. Proportions of use were assessed over time. Multivariable logistic regression modeling was performed to assess factors associated with receiving rituximab for an FDA-approved indication.RESULTS: A total of 1,674 patients were included. The majority (66.4%) of patients had an FDA-approved indication, with lymphoma being the most common approved indication (66.4%). The most common indication for off-label use was neurologic conditions (72.7%), predominantly demyelinating diseases. Off-label indication use increased from 1.2% in 2009 to 55.6% in 2017. Factors associated with rituximab use for an FDA-approved indication included increased age (adjusted odds ratio [AOR] = 1.05, 95% CI = 1.04-1.07) and increased burden of chronic disease (chronic disease score: AOR = 1.07, 95% CI = 1.02-1.12; Charlson Comorbidity Index score: AOR = 3.52, 95% CI = 3.03-4.10).CONCLUSIONS: Off-label use of rituximab grew dramatically over the course of the study. With the recent FDA approval of the rituximab biosimilar and its expected lower price, off-label use will likely continue to rise. Opportunities for cost savings and to ensure appropriate use of these medications should be evaluated.
Robust and accurate behavioral tracking is essential for ethological studies. Common methods for tracking and extracting behavior rely on user adjusted heuristics that can significantly vary across different individuals, environments, and experimental conditions. As a result, they are difficult to implement in large-scale behavioral studies with complex, heterogenous environmental conditions. Recently developed deep-learning methods for object recognition such as Faster R-CNN have advantages in their speed, accuracy, and robustness. Here, we show that Faster R-CNN can be employed for identification and detection of Caenorhabditis elegans in a variety of life stages in complex environments. We applied the algorithm to track animal speeds during development, fecundity rates and spatial distribution in reproductive adults, and behavioral decline in aging populations. By doing so, we demonstrate the flexibility, speed, and scalability of Faster R-CNN across a variety of experimental conditions, illustrating its generalized use for future large-scale behavioral studies.
While our sample did not demonstrate species differences in the degree of spatial autocorrelation of elastic moduli, there may be mechanical effects of heterogeneity (relative strength and rigidity) that do distinguish at the species or subfamilial level (i.e., colobines vs. cercopithecines). The potential connections of heterogeneity to diet and/or taxonomy remain to be discovered.
Free or low-cost Internet-based initiatives can improve access to the medical literature in LIC. Open access journals are a key component to providing clinically relevant literature to the regions and healthcare workers who need it most.
ImportanceDrug expenditures in the US are higher than in any other country and are projected to continue increasing, so US health systems may benefit from evaluating international regulatory and reimbursement decision-making of new drugs.ObjectiveTo evaluate regulatory decisions and health technology assessments (HTAs) in Australia, Canada, and the UK regarding new drugs approved by the US Food and Drug Administration (FDA) in 2017 through 2020, as well as to estimate the US cost per patient per year for drugs receiving negative recommendations.Design and SettingIn this cross-sectional study, recommendations issued by agencies in Australia, Canada, and the UK were collected for new drugs approved by the FDA in 2017 through 2020. All data were current as of May 31, 2022.ExposuresAuthorizations and HTAs in selected countries.Main Outcomes and MeasuresAll FDA-approved drugs were matched by active ingredient to decision summary reports published by drug regulators and HTA agencies in Australia, Canada, and the UK. Regulatory approval concordance and reasons for negative recommendations were assessed using descriptive statistics. For drugs not recommended by an international agency, the annual US drug cost per patient was estimated from FDA labeling and wholesale acquisition costs.ResultsThe FDA approved 206 new drugs in 2017 through 2020, of which 162 (78.6%) were granted marketing authorization by at least 1 other regulatory agency at a median (IQR) delay of 12.1 (17.7) months following US approval. Conversely, 5 FDA-approved drugs were refused marketing authorization by an international regulatory agency due to unfavorable benefit-to-risk assessments. An additional 42 FDA-approved drugs received negative reimbursement recommendations from HTA agencies in Australia, Canada, or the UK due to uncertainty of clinical benefits or unacceptably high prices. The median (IQR) US cost of the 47 drugs refused authorization or not recommended for reimbursement by an international agency was $115 281 ($166 690) per patient per year. Twenty drugs were for oncology indications, and 36 were approved by the FDA through expedited regulatory pathways or the Orphan Drug Act.Conclusions and RelevanceThis cross-sectional study assessed reasons for which drugs recently approved by the FDA were refused marketing authorization or not recommended for public reimbursement in other countries. Drugs with limited international market presence may require close examination by US health care professionals and health systems.
3552 Background: Bevacizumab-awwb was the first biosimilar approved by the U.S. Food and Drug Administration (FDA) for treatment of cancer and became available for use in July 2019. Clinical comparative efficacy and safety of bevacizumab-awwb to bevacizumab was established in a single study of adult patients with advanced non-squamous non-small cell lung cancer. Approval based on extrapolation was granted by the FDA for all other indications, including metastatic colorectal cancer (mCRC). The objective of this study was to evaluate the real-world effectiveness and safety outcomes of patients with mCRC initiated on bevacizumab-awwb versus bevacizumab in an integrated healthcare delivery system. Methods: This was an observational cohort study of patients with mCRC in Kaiser Permanente California, Colorado, and Mid-Atlantic States who were initiated on bevacizumab-awwb between July 2019 and March 2020 or reference bevacizumab between July 2015 and June 2018. Patients with history of bevacizumab use in the 6 months prior to the index treatment date were excluded. Patients were followed until 12 months after treatment initiation, end of plan membership, or death, whichever occurred first. The primary outcome of overall survival (OS) was analyzed using a non-inferiority test with lower margin of 10% and Cox proportional-hazards modeling. Secondary outcomes included count of doses received, treatment duration, all-cause hospitalizations, and incidence of serious adverse events. Results: A total of 1,445 patients initiated on either bevacizumab-awwb (n=239) or bevacizumab (n=1,206) were included in the analysis. The mean overall age was 60 ± 13 years and 54% of patients were male. The OS rate was 72.8% and 73.1% for patients receiving bevacizumab-awwb and bevacizumab, respectively ( p<0.01 for non-inferiority). The adjusted hazard ratio for mortality was 1.01 (0.77-1.33, p=0.93). There were no statistically significant differences in secondary outcomes between the 2 study groups (Table). Conclusions: Bevacizumab-awwb is a safe and effective option when compared to the reference bevacizumab in the treatment of mCRC. Future studies should evaluate outcomes after longer follow-up time and in different cancer types. [Table: see text]
The purpose of this study is to develop candidate common data element (CDE) items related to clinical staff training in long-term care (LTC) homes that can be used to enable international comparative research. This paper is part of the WE-THRIVE ( Worldwide Elements to Harmonize Research in Long-Term Care Li ving Environments) group’s initiative which aims to improve international academic collaboration. We followed best practices to develop CDEs by conducting a literature review of clinical staff (i.e., Regulated Nurses, Health Care Aides) training measures, and convening a subgroup of WE-THRIVE experts to review the literature review results to develop suitable CDEs. The international expert panel discussed and critically reflected on the current knowledge gaps from the literature review results. The panel proposed three candidate CDEs which focused on the presence of and the measurement of training. These three proposed CDEs seek to facilitate international research as well as assist in policy and decision-making regarding LTC homes worldwide. This study is a critical first step to develop candidate CDE items to measure staff training internationally. Further work is required to get feedback from other researchers about the proposed CDEs, and assess the feasibility of these CDEs in high and low resourced settings.
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