Are They Prepared? Comparing Intern Milestone Performance of Accelerated 3-Year and 4-Year Medical Graduates.

PURPOSE: Accelerated 3-year programs (A3YPs) at medical schools were developed to address student debt and mitigate workforce shortage issues. This study investigated whether medical school length (3 vs 4 years) was associated with early residency performance. The primary research question was as follows: Are the Accreditation Council for Graduate Medical Education Milestones (MS) attained by A3YP graduates comparable to graduates of traditional 4-year programs (T4YPs) at 6 and 12 months into internship? METHOD: The MS data from students entering U.S. medical schools in 2021 and 2022 from the 6 largest specialties were used: emergency medicine, family medicine, internal medicine, general surgery, psychiatry, and pediatrics. Three-year and 4-year graduates were matched for analysis (2,899 matched learners: 182 in A3YPs and 2,717 in T4YPs). The study used a noninferiority study design to examine data trends between the study cohort (A3YP) and control cohort (T4YP). To account for medical school and residency program effects, the authors used cross-classified random-effects regression to account for clustering and estimate group differences. RESULTS: The mean Harmonized MS ratings for the midyear and end-year reporting periods showed no significant differences between the A3YP and T4YP groups (mean [SE] cross-classified coefficient = 0.01 [0.02], P = .77). Mean MS ratings across internal medicine MS for the midyear and end-year reporting periods showed no significant differences between the A3YP and T4YP groups (mean [SE] cross-classified coefficient = -0.03 [0.03], P = .31). Similarly, for family medicine, there were no statistically significant differences between the A3YP and T4YP groups (mean [SE] cross-classified coefficient = 0.01 [0.02], P = .96). CONCLUSIONS: For the specialties studied, there were no significant differences in MS performance between 3-year and 4-year graduates at 6 and 12 months into internship. These results support comparable efficacy of A3YPs in preparing medical students for residency.

MiR-423-5p prevents MALAT1-mediated proliferation and metastasis in prostate cancer.

BACKGROUND: The long non-coding RNA (lncRNA), MALAT1, plays a key role in the development of different cancers, and its expression is associated with worse prognosis in patients. However, its mechanism of action and its regulation are not well known in prostate cancer (PCa). A general mechanism of action of lncRNAs is their interaction with other epigenetic regulators including microRNAs (miRNAs). METHODS: Using lentiviral stable miRNA transfection together with cell biology functional assays and gene expression/target analysis, we investigated the interaction between MALAT1 and miR-423-5p, defined as a target with in silico prediction analysis, in PCa. RESULTS: Through bioinformatic analysis of data available from TCGA, we have found that MALAT1 expression correlates with high Gleason grade, metastasis occurrence, and reduced survival in PCa patients. These findings were validated on a TMA of PCa showing a significant correlation between MALAT1 expression with both stage and grading. We report that, in PCa cells, MALAT1 expression and activity is regulated by miR-423-5p that binds MALAT1, downregulates its expression and inhibits its activity in promoting proliferation, migration, and invasion. Using NanoString analysis, we unraveled downstream cell pathways that were affected by miR-423-5p expression and MALAT1 downregulation and identified several alterations in genes that are involved in metastatic response and angiogenic pathways. In addition, we showed that the overexpression of miR-423-5p increases survival and decreases metastases formation in a xenograft mouse model. CONCLUSIONS: We provide evidence on the role of MALAT1 in PCa tumorigenesis and progression. Also, we identify a direct interaction between miR-423-5p and MALAT1, which results in the suppression of MALAT1 action in PCa.

Treatment Strategies for GLILD in Common Variable Immunodeficiency: A Systematic Review.

Introduction: Besides recurrent infections, a proportion of patients with Common Variable Immunodeficiency Disorders (CVID) may suffer from immune dysregulation such as granulomatous-lymphocytic interstitial lung disease (GLILD). The optimal treatment of this complication is currently unknown. Experienced-based expert opinions have been produced, but a systematic review of published treatment studies is lacking. Goals: To summarize and synthesize the published literature on the efficacy of treatments for GLILD in CVID. Methods: We performed a systematic review using the PRISMA guidelines. Papers describing treatment and outcomes in CVID patients with radiographic and/or histologic evidence of GLILD were included. Treatment regimens and outcomes of treatment were summarized. Results: 6124 papers were identified and 42, reporting information about 233 patients in total, were included for review. These papers described case series or small, uncontrolled studies of monotherapy with glucocorticoids or other immunosuppressants, rituximab monotherapy or rituximab plus azathioprine, abatacept, or hematopoietic stem cell transplantation (HSCT). Treatment response rates varied widely. Cross-study comparisons were complicated because different treatment regimens, follow-up periods, and outcome measures were used. There was a trend towards more frequent GLILD relapses in patients treated with corticosteroid monotherapy when compared to rituximab-containing treatment regimens based on qualitative endpoints. HSCT is a promising alternative to pharmacological treatment of GLILD, because it has the potential to not only contain symptoms, but also to resolve the underlying pathology. However, mortality, especially among immunocompromised patients, is high. Conclusions: We could not draw definitive conclusions regarding optimal pharmacological treatment for GLILD in CVID from the current literature since quantitative, well-controlled evidence was lacking. While HSCT might be considered a treatment option for GLILD in CVID, the risks related to the procedure are high. Our findings highlight the need for further research with uniform, objective and quantifiable endpoints. This should include international registries with standardized data collection including regular pulmonary function tests (with carbon monoxide-diffusion), uniform high-resolution chest CT radiographic scoring, and uniform treatment regimens, to facilitate comparison of treatment outcomes and ultimately randomized clinical trials.

Genetic, epigenetic and microbiome characterisation of an earthworm species (Octolasion lacteum) along a radiation exposure gradient at Chernobyl.

The effects of exposure to different levels of ionising radiation were assessed on the genetic, epigenetic and microbiome characteristics of the "hologenome" of earthworms collected at sites within the Chernobyl exclusion zone (CEZ). The earthworms Aporrectodea caliginosa (Savigny, 1826) and Octolasion lacteum (Örley, 1881) were the two species that were most frequently found at visited sites, however, only O. lacteum was present at sufficient number across different exposure levels to enable comparative hologenome analysis. The identification of morphotype O. lacteum as a probable single clade was established using a combination of mitochondrial (cytochrome oxidase I) and nuclear genome (Amplified Fragment Length Polymorphism (AFLP) using MspI loci). No clear site associated differences in population genetic structure was found between populations using the AFLP marker loci. Further, no relationship between ionising radiation exposure levels and the percentage of methylated loci or pattern of distribution of DNA methylation marks was found. Microbiome structure was clearly site dependent, with gut microbiome community structure and diversity being systematically associated with calculated site-specific earthworm dose rates. There was, however, also co-correlation between earthworm dose rates and other soil properties, notably soil pH; a property known to affect soil bacterial community structure. Such co-correlation means that it is not possible to attribute microbiome changes unequivocally to radionuclide exposure. A better understanding of the relationship between radionuclide exposure soil properties and their interactions on bacterial microbiome community response is, therefore, needed to establish whether these the observed microbiome changes are attributed directly to radiation exposure, other soil properties or to an interaction between multiple variables at sites within the CEZ.

Cost Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Relapsed or Refractory Pediatric B-Cell Acute Lymphoblastic Leukemia.

PURPOSE: The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel was recently approved to treat relapsed or refractory pediatric acute lymphoblastic leukemia. With a one-time infusion cost of $475,000, tisagenlecleucel is currently the most expensive oncologic therapy. We aimed to determine whether tisagenlecleucel is cost effective compared with currently available treatments. METHODS: Markov modeling was used to evaluate tisagenlecleucel in pediatric relapsed or refractory acute lymphoblastic leukemia from a US health payer perspective over a lifetime horizon. The model was informed by recent multicenter, single-arm clinical trials. Tisagenlecleucel (under a range of plausible long-term effectiveness) was compared with blinatumomab, clofarabine combination therapy (clofarabine, etoposide, and cyclophosphamide), and clofarabine monotherapy. Scenario and probabilistic sensitivity analyses were used to explore uncertainty. Main outcomes were life-years, discounted lifetime costs, discounted quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (3% discount rate). RESULTS: With an assumption of a 40% 5-year relapse-free survival rate, tisagenlecleucel increased life expectancies by 12.1 years and cost $61,000/QALY gained. However, at a 20% 5-year relapse-free survival rate, life-expectancies were more modest (3.8 years) and expensive ($151,000/QALY gained). At a 0% 5-year relapse-free survival rate and with use as a bridge to transplant, tisagenlecleucel increased life expectancies by 5.7 years and cost $184,000/QALY gained. Reduction of the price of tisagenlecleucel to $200,000 or $350,000 would allow it to meet a $100,000/QALY or $150,000/QALY willingness-to-pay threshold in all scenarios. CONCLUSION: The long-term effectiveness of tisagenlecleucel is a critical but uncertain determinant of its cost effectiveness. At its current price, tisagenlecleucel represents reasonable value if it can keep a substantial fraction of patients in remission without transplantation; however, if all patients ultimately require a transplantation to remain in remission, it will not be cost effective at generally accepted thresholds. Price reductions would favorably influence cost effectiveness even if long-term clinical outcomes are modest.

Estradiol signaling mediates gender difference in visceral adiposity via autophagy.

Excessive adiposity (particularly visceral fat mass) increases the risks of developing metabolic syndrome. Women have lower deposit of visceral fat than men, and this pattern becomes diminished postmenopausally, but the underlying mechanism remains largely unknown. Here, we show that the gender difference in visceral fat distribution is controlled by an estradiol-autophagy axis. In C57BL/6J and wild-type control mice, a higher visceral fat mass was detected in the males than in the females, which was associated with lower expression of estrogen receptor α (ERα) and more active autophagy in males vs. females. However, deletion of ERα normalized autophagy activity and abolished the gender difference in visceral adiposity. In line with the adiposity-reducing effect of the ERα-autophagy axis, we found that downregulation of ERα and increased autophagy activity were required for adipogenesis, while induction of estradiol signaling dampened autophagy and drastically prevented adipogenesis. Mechanistically, the estradiol-ERα signaling activated mTOR, which phosphorylated and inhibited ULK1, thereby suppressing autophagy and adipogenesis. Together, our study suggests that the lower visceral adiposity in the females (vs. the males) arises from a more active estradiol-ERα signaling, which tunes down autophagy and adipogenesis.

Diazoxon disrupts the expression and distribution of ßIII-tubulin and MAP 1B in differentiating N2a cells.

This study aimed at assessing the effects of diazoxon (DZO), a major metabolite of the insecticide diazinon (DZ), on key cytoskeletal proteins in differentiating N2a neuroblastoma cells. Initial experiments established that sublethal concentrations of 1, 5 and 10 µM DZO produced profound inhibition of neurite outgrowth. Densitometric scanning of probed immunoblots of N2a cell lysates demonstrated that DZO had no effect on total ß-tubulin levels. However, probing with a monoclonal antibody that recognised specifically the ßIII-tubulin isotype revealed that 10 µM DZO induced a significant reduction in the levels of this particular form. Levels of polyglutamylated tubulin were not altered. Exposure to 10 µM DZO also decreased the expression of microtubule-associated protein 1B (MAP 1B). However, DZO had no effect on the expression of MAP tau. DZO also failed to affect the levels neurofilament light (NFL) and neurofilament medium (NFM) chain levels. Indirect immunofluorescence demonstrated that the staining of neurites in treated cells was weaker than in the controls for ßIII-tubulin. In conclusion, DZO disrupts the microtubule (MT) network affecting the expression and distribution of two specific MT proteins known to be important in neuritogenesis. DZO may contribute to the developmental neurotoxicity seen following exposure to DZ.

Resveratrol, a polyphenolic phytostilbene, inhibits endothelial monocyte chemotactic protein-1 synthesis and secretion.

BACKGROUND/AIMS: Resveratrol is a naturally occurring polyphenol phytoestrogen and one of several constituents of red wine thought to be cardioprotective. We investigated the effect of resveratrol on the expression of the atherogenic chemokine, monocyte chemotactic protein-1 (MCP-1). METHODS: Human umbilical vein endothelial cells were stimulated with interleukin-1beta (IL-1beta) in the absence or presence of resveratrol. MCP-1 levels were determined by ELISA and MCP-1 mRNA was measured. RESULTS: Resveratrol (1-100 microM) dose-dependently inhibited IL-1beta-stimulated MCP-1 secretion, with approximately 45% inhibition at 50 microM resveratrol. This was a Gi-protein- and NO-dependent effect. Resveratrol also significantly inhibited MCP-1 gene expression in a Gi-protein-dependent but NO-independent manner. While resveratrol had no effect on MCP-1 mRNA degradation, it inhibited MCP-1 promoter activity and reduced nuclear factor kappaB and activator protein-1 binding activity induced by IL-1beta. Moreover, while hemoxygenase-1 (HO-1) expression was induced by resveratrol in human umbilical vein endothelial cells, neither treatment with the HO-1 inhibitor tin-protoporphyrin IX nor siRNA-directed knockdown of HO-1 had any effect on the inhibition of MCP-1 mRNA or protein secretion by resveratrol. CONCLUSION: These data demonstrate an inhibitory effect of resveratrol on MCP-1 synthesis and secretion, mediated via distinct signaling pathways. The inhibition of MCP-1 may represent a novel cardioprotective mechanism of resveratrol.