Under the 2022 Inflation Reduction Act, the Centers for Medicare and Medicaid Services (CMS) are able to negotiate prices for topselling drugs in the Medicare Part B and D programs. In determining ...initial price offers, CMS will compare the prices and clinical benefits of the drugs subject to negotiation to the prices and clinical benefits of therapeutic alternatives. Despite the central role that the selection of therapeutic alternatives will play in the price negotiations, the available guidance published by CMS provides few details about how the organization will undertake this process, which will be particularly complex for drugs approved for more than one indication. To better inform the selection process, we identified all US Food and Drug Administration-approved indications for the first 10 drugs subject to negotiation. Using 2020-2021 Medicare claims data, we identified Medicare Part D beneficiaries using each of the 10 drugs. We extracted medical claims with diagnosis codes for each of the approved indications to report the relative treated prevalence of use by indication for each drug. We reviewed published clinical guidelines to identify relevant therapeutic alternatives for each of the indications. We integrated the evidence on the relative treated prevalence of indications and clinical guidelines to propose therapeutic alternatives for each of the 10 drugs. We describe challenges that CMS may face in selecting therapeutic alternatives.
Cord blood transplantation (CBT) is associated with low risk of leukemia relapse. Mechanisms underlying antileukemia benefit of CBT are not well understood, however a previous study strongly but ...indirectly implicated cells from the mother of the cord blood (CB) donor. A fetus acquires a small number of maternal cells referred to as maternal microchimerism (MMc) and MMc is sometimes detectable in CB. From a series of 95 patients who underwent double or single CBT at our center, we obtained or generated HLA-genotyping of CB mothers in 68. We employed a technique of highly sensitive HLA-specific quantitative-PCR assays targeting polymorphisms unique to the CB mother to assay CB-MMc in patients post-CBT. After additional exclusion criteria, CB-MMc was evaluated at multiple timepoints in 36 patients (529 specimens). CB-MMc was present in seven (19.4%) patients in bone marrow, peripheral blood, innate and adaptive immune cell subsets, and was detected up to 1-year post-CBT. Statistical trends to lower relapse, mortality, and treatment failure were observed for patients with vs. without CB-MMc post-CBT. Our study provides proof-of-concept that maternal cells of the CB graft can be tracked in recipients post-CBT, and underscore the importance of further investigating CB-MMc in sustained remission from leukemia following CBT.
Bidirectional exchange of cells between mother and fetus establishes microchimerism (Mc). Mc can persist for decades and is associated with later-life health and disease. Greater fetal Mc is detected ...in the maternal compartment in preeclampsia (PE), but whether maternal Mc (MMC) in umbilical cord blood (CB) is altered in PE is unknown. We evaluated MMc in CB from normal and PE pregnancies. DNA from CB mononuclear cells following placental delivery (n = 36 PE, n = 37 controls) and maternal blood was extracted and genotyped. MMc, quantified by qPCR assays targeting maternal-specific nonshared polymorphisms in CB, was compared using logistic and negative binomial regression models. Clinically and statistically relevant confounders were included, and included the total number of cell equivalents tested, gravidity, mode of delivery, birthweight, and fetal sex. PE participants delivered at earlier gestational ages, with higher Cesarean rates, and lower infant birthweights. CB MMc detection was similar between PE and controls (52.8% vs. 51.3%, respectively, p = 0.90) and unchanged after adjustment for confounders. MMc concentration was not different between groups (mean 73.7 gEq/10
gEq in PE vs. mean 22.8 gEq/10
in controls, p = 0.56), including after controlling for confounders (p = 0.64). There was no difference in CB MMc detection or concentration between PE and normal pregnancies, despite previously noted greater fetal Mc in the maternal compartment. This suggests possible differential transfer of cells at the maternal fetal interface in PE. Phenotypic evaluation of Mc cells may uncover underlying mechanisms for differential cellular exchange between mother and fetus in PE.
Objective
To compare fetal microchimerism (FMc) in pregnancies with uncomplicated vaginal delivery (VD) versus caesarean delivery (CD).
Design
Prospective cohort study.
Setting
University of ...Washington and Fred Hutchinson Cancer Research Center, USA.
Population
Women delivering singleton pregnancies without pertinent antenatal complications with uncomplicated deliveries (n = 36).
Methods
We collected maternal predelivery, postdelivery and umbilical cord blood for each mother–baby pair. Following maternal and fetal genotyping, FMc was measured with quantitative polymerase chain reaction assays targeting fetus‐specific polymorphisms. Quantification of FMc is expressed as genome equivalents (gEq) of fetal DNA/100 000 total gEq tested. FMc detection was evaluated by logistic regression while controlling for total number of cell equivalents tested and clinically relevant covariates. FMc concentrations were compared using negative binomial regression while controlling for the same covariates and predelivery FMc positivity.
Main outcome measure
Detection and concentration of FMc by mode of delivery.
Results
Twenty‐four mother–baby pairs had a VD and 12 had a CD. Postdelivery FMc detection was higher following CD than after VD (58.3% versus 16.7%, P = 0.02). After controlling for covariates, the likelihood of postdelivery FMc detection was almost nine‐fold higher after CD than VD (odds ratio 8.8, 95% CI 1.6–47.6; P = 0.01). With respect to postdelivery FMc concentration, the detection rate ratio for CD versus VD in the adjusted negative binomial regression model was 14.7 (95% CI 3.2–66.8; P = 0.001).
Conclusion
Postdelivery peripheral FMc detection and concentration are significantly higher after CD than after VD. As FMc is associated with long‐term maternal health, our findings suggest that the mode of delivery may impact this risk.
Tweetable
Greater fetal microchimerism found in maternal blood following caesarean delivery compared with vaginal delivery.
Tweetable
Greater fetal microchimerism found in maternal blood following caesarean delivery compared with vaginal delivery.
We report on efforts to measure readiness to adopt opioid safety initiatives in community pharmacies within 2 large chains. Previous studies identified lack of knowledge, confidence, or enthusiasm in ...addressing harm reduction efforts. We implemented an intervention that provided training to improve opioid safety. The goal was to increase naloxone prescribing and nonprescription syringe sales, reduce stigma, and decrease opioid overdoses among patients and customers.
To assess pharmacy readiness for intervention delivery, by characterizing pharmacy culture around opioid safety; describing current practices and challenges interacting with patients and customers on naloxone, nonprescription syringe sales, and buprenorphine; and determining pharmacy defined goals for implementing the intervention.
The sample included pharmacy managers and staff pharmacists from 2 large chains who completed a brief phone interview. Interviews consisted of Likert-scale and open-ended, theoretically driven questions. Questions focused on workplace culture, patient engagement, naloxone and buprenorphine prescribing, nonprescription syringe sales, and intervention goals. Coding categories for the open-ended questions were derived using a thematic review of responses.
A total of 163 respondents described both workplace culture and how they encourage patient opioid safety as including public health awareness, patient engagement, and naloxone prescribing. Sale of nonprescription syringes exhibited high variability: no sales barriers (53.9%), sales with barriers (21.5%), and no sales (20.9%). Half of pharmacists (50.3%) interacted with buprenorphine prescribers outside of medication fills. Most respondents (68.7%) endorsed being ready to promote the intervention. Pharmacists named goals in adopting the intervention of wanting more knowledge and educational materials, talking points with patients, and best practices for offering naloxone.
Community pharmacists, before implementation, described awareness of and receptiveness to opioid safety initiatives, with substantial barriers around nonprescription syringe sales. Assessed knowledge level, culture, and identified barriers that emerged in the readiness assessments can be used to tailor future pharmacy-specific programming.
Background
Sickle cell disease (SCD) is a complex genetic disorder that manifests in infancy and progresses throughout life in the form of acute and chronic complications. As the upfront costs of ...potentially curative, genetic therapies will likely be high, an assessment and comprehensive characterization of the medical and non-medical cost burden will inform future decision making.
Objective
We sought to systematically summarize the existing literature surrounding SCD medical and non-medical costs.
Methods
We searched MEDLINE and EMBASE (2008–2020) and identified US-based studies that detailed medical or non-medical costs. Eligible studies provided empirical estimates about any aspect of cost or SCD individuals of all ages and their caregivers. Study quality was assessed using the Newcastle–Ottawa Scale, and costs were adjusted to 2019 US$.
Results
Search queries returned 479 studies, with 342 from medical burden searches and 137 from non-medical burden searches, respectively. Herein, we report the results of the 40 studies that contained relevant cost information: 39 detailed medical costs and 1 detailed non-medical costs. Costs were higher for SCD patients when compared with non-SCD individuals (cost difference range: $6636–$63,436 annually). The highest medical cost component for SCD patients was inpatient ($11,978–$59,851 annually), followed by outpatient and then pharmacy. No studies characterized the cost burden throughout the lifetime disease trajectory of an SCD individual, and no studies captured caregiver or productivity costs.
Conclusion
Our results reveal an incomplete characterization of medical and non-medical costs within SCD. A deeper understanding of the medical and non-medical cost burden requires completion of additional studies that capture the burden across the patient’s lifetime, in addition to expression of the impact of existing and emergent health technologies on disease trajectory.
Glycogen synthase kinase 3 (GSK3) is a critical enzyme in neuronal physiology; however, it is not yet known whether it has any specific role in presynaptic function. We found that GSK3 phosphorylates ...a residue on the large GTPase dynamin I (Ser-774) both in vitro and in primary rat neuronal cultures. This was dependent on prior phosphorylation of Ser-778 by cyclin-dependent kinase 5. Using both acute inhibition with pharmacological antagonists and silencing of expression with short hairpin RNA, we found that GSK3 was specifically required for activity-dependent bulk endocytosis (ADBE) but not clathrin-mediated endocytosis. Moreover we found that the specific phosphorylation of Ser-774 on dynamin I by GSK3 was both necessary and sufficient for ADBE. These results demonstrate a presynaptic role for GSK3 and they indicate that a protein kinase signaling cascade prepares synaptic vesicles for retrieval during elevated neuronal activity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We previously identified the protein Lbh as necessary for cranial neural crest (CNC) cell migration in Xenopus through the use of morpholinos. However, Lbh is a maternally deposited protein and ...morpholinos achieve knockdowns through prevention of translation. In order to investigate the role of Lbh in earlier embryonic events, we employed the new technique “Trim-Away” to degrade this maternally deposited protein. Trim-Away utilizes the E3 ubiquitin ligase trim21 to degrade proteins targeted with an antibody and was developed in mammalian systems. Our results show that Xenopus is amenable to the Trim-Away technique. We also show that early knockdown of Lbh in Xenopus results in defects in gastrulation that present with a decrease in fibronectin matrix assembly, an increased in mesodermal cell migration and decrease in endodermal cell cohesion. We further show that the technique is also effective on a second abundant maternal protein PACSIN2. We discuss potential advantages and limit of the technique in Xenopus embryos as well as the mechanism of gastrulation inhibition.
•Trim-Away can be used to specifically know down maternal protein in Xenopus.•The speed of Trim Away mediated knock down is dictated by the antibody-antigen pair.•The defects observed with Trim Away recapitulate defect observed using Morpholino knock down and dominant negative construct.•The Trim Away mediated loss of Lbh lead to severed gastrulation defects.
PDF
