Births in the United States, 2023.

Objectives: This report presents 2023 data on U.S. births compared with 2022 and 2021 for several key demographic and maternal and infant characteristics. Methods: Descriptive tabulations of data reported on the birth certificates of the 3.60 million births that occurred in 2023 are presented. Data are presented for the number of births, the general fertility rate, teenage birth rates, the distribution of births by trimester prenatal care began and the distribution of births by selected gestational age categories. Data for 2023 are compared with data for 2022 and 2021. Results: A total of 3,596,017 births were registered in the United States in 2023, down 2% from 2022. The general fertility rate declined 3% in 2023 to 54.5 births per 1,000 females ages 15-44. Birth rates declined for females ages 15-19 (4%), 15-17 (2%), and 18-19 (5%), from 2022 to 2023. The percentage of mothers receiving prenatal care in the first trimester of pregnancy declined 1% to 76.1% in 2023 while the percentage of mothers with no prenatal care increased 5%. The preterm birth rate was essentially unchanged at 10.41% in 2023 but the rate of early term births rose 2%.

Oral pharmacokinetics and efficacy of oral phospholipid remdesivir nucleoside prodrugs against SARS-CoV-2 in mice.

Oral broad-spectrum antivirals are urgently needed for the treatment of many emerging and contemporary RNA viruses. We previously synthesized 1-O-octadecyl-2-O-benzyl-sn-glyceryl-P-RVn (ODBG-P-RVn, V2043), a phospholipid prodrug of GS-441524 (remdesivir nucleoside, RVn), and demonstrated its in vivo efficacy in a SARS-CoV-2 mouse model. Structure-activity relationship studies focusing on the prodrug scaffold identified two modifications, 3-fluoro-4-methoxy-benzyl (V2053) and 4-cyano-benzyl (V2067), that significantly enhanced the in vitro broad-spectrum antiviral activity against multiple RNA viruses when compared to V2043. Here, we demonstrate that V2043, V2053, and V2067 are all orally bioavailable, well-tolerated, and achieve high sustained plasma levels after single oral daily dosing. All three phospholipid prodrugs are significantly more active than RVn in vitro and significantly reduce SARS-CoV-2 lung titers in prophylaxis and treatment mouse models of SARS-CoV-2 B.1.351 infection. On a molar basis, V2043 and V2067 are substantially more active than obeldesivir/GS-5245 and molnupiravir in vivo. Together, these data support the continued development of phospholipid RVn prodrugs for the treatment of SARS-CoV-2 and other RNA viruses of clinical concern.

Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer.

BACKGROUND: Outcomes in patients with hormone receptor-positive metastatic breast cancer worsen after one or more lines of endocrine-based therapy. Trastuzumab deruxtecan has shown efficacy in patients with metastatic breast cancer with low expression of human epidermal growth factor receptor 2 (HER2) after previous chemotherapy. METHODS: We conducted a phase 3, multicenter, open-label trial involving patients with hormone receptor-positive metastatic breast cancer with low HER2 expression (a score of 1+ or 2+ on immunohistochemical [IHC] analysis and negative results on in situ hybridization) or ultralow HER2 expression (IHC 0 with membrane staining) who had received one or more lines of endocrine-based therapy and no previous chemotherapy for metastatic breast cancer. Patients were randomly assigned in a 1:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival (according to blinded independent central review) among the patients with HER2-low disease. Secondary end points included progression-free survival among all the patients who had undergone randomization, overall survival, and safety. RESULTS: Of the 866 patients who underwent randomization, 713 had HER2-low disease, and 153 had HER2-ultralow disease. Among the patients with HER2-low disease, the median progression-free survival was 13.2 months (95% confidence interval [CI], 11.4 to 15.2) in the trastuzumab deruxtecan group and 8.1 months (95% CI, 7.0 to 9.0) in the chemotherapy group (hazard ratio for disease progression or death, 0.62; 95% CI, 0.51 to 0.74; P<0.001); the results were consistent in the exploratory HER2-ultralow population. Data for overall survival were immature. Adverse events of grade 3 or higher occurred in 52.8% of the patients in the trastuzumab deruxtecan group and in 44.4% of those in the chemotherapy group. Adjudicated interstitial lung disease or pneumonitis occurred in 49 patients (11.3%; three events were grade 5 in severity) and in 1 patient (0.2%; grade 2), respectively. CONCLUSIONS: Among patients with hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer who had received one or more lines of endocrine-based therapy, treatment with trastuzumab deruxtecan resulted in longer progression-free survival than chemotherapy. No new safety signals were identified. (Funded by AstraZeneca and Daiichi Sankyo; DESTINY-Breast06 ClinicalTrials.gov number, NCT04494425.).

Chlamydia trachomatis modulates the expression of JAK-STAT signaling components to attenuate the type II interferon response of epithelial cells.

Chlamydia trachomatis has adapted to subvert signaling in epithelial cells to ensure successful intracellular development. Interferon-γ (IFNγ) produced by recruited lymphocytes signals through the JAK/STAT pathway to restrict chlamydial growth in the genital tract. However, during Chlamydia infection in vitro, addition of IFNγ does not fully induce nuclear localization of its transcription factor STAT1 and expression of its target gene, IDO1. We hypothesize that this altered interferon response is a result of Chlamydia targeting components of the IFNγ-JAK/STAT pathway. To assess the ability of replicating Chlamydia to dampen interferon signaling, HEp2 human epithelial cells were infected with C. trachomatis serovar L2 for 24 hours prior to exposure to physiologically relevant levels of IFNγ (500 pg/mL). This novel approach enabled us to observe reduced phospho-activation of both STAT1 and its kinase Janus Kinase 2 (JAK2) in infected cells compared with mock-infected cells. Importantly, basal JAK2 and STAT1 transcript and protein levels were dampened by infection even in the absence of interferon, which could have implications for cytokine signaling beyond IFNγ. Additionally, target genes IRF1, GBP1, APOL3, IDO1, and SOCS1 were not fully induced in response to IFNγ exposure. Infection-dependent decreases in transcript, protein, and phosphoprotein were rescued when de novo bacterial protein synthesis was inhibited with chloramphenicol, restoring expression of IFNγ-target genes. Similar Chlamydia-dependent dampening of STAT1 and JAK2 transcript levels was observed in infected HeLa and END1 endocervical cells and in HEp2s infected with C. trachomatis serovar D, suggesting a conserved mechanism of dampening the interferon response by reducing the availability of key signaling components. IMPORTANCE: As an obligate intracellular pathogen that has evolved to infect the genital epithelium, Chlamydia has developed strategies to prevent detection and antimicrobial signaling in its host to ensure its survival and spread. A major player in clearing Chlamydia infections is the inflammatory cytokine interferon-γ (IFNγ), which is produced by immune cells that are recruited to the site of infection. Reports of IFNγ levels in endocervical specimens from Chlamydia-infected patients range from 1 to 350 pg/mL, while most in vitro studies of the effects of IFNγ on chlamydial growth have used 15-85-fold higher concentrations. By using physiologically relevant concentrations of IFNγ, we were able to assess Chlamydia's ability to modulate its signaling. We found that Chlamydia decreases the expression of multiple components that are required for inducing gene expression by IFNγ, providing a possible mechanism by which Chlamydia trachomatis can attenuate the immune response in the female genital tract to cause long-term infections.

A multicenter, retrospective study of a through-the-needle injection-capable electrosurgical knife for endoscopic submucosal dissection.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) is a technically challenging resection technique for en bloc removal of dysplastic and early cancerous GI lesions. We conducted a single-arm retrospective study evaluating the safety and efficacy of a new through-the-needle injection-capable electrosurgical knife used in upper and lower ESD procedures performed at 6 U.S. academic centers. METHODS: Data were retrospectively collected on consecutive cases in which the new ESD knife was used. The primary efficacy endpoint was successful ESD (en bloc resection with negative margins). Secondary efficacy endpoints included en bloc resection rate, curative resection rate, median ESD time, and median dissection speed. The safety endpoint was device- or procedure-related serious adverse events. RESULTS: ESD procedures of 581 lesions in 579 patients were reviewed, including 187 (32.2%) upper GI and 394 (67.8%) lower GI lesions. Prior treatment was reported in 283 (48.9%) patients. Successful ESD was achieved in 477 (82.1% of 581) lesions-lower for patients with versus without submucosal fibrosis (73.6% vs 87.0%, respectively; P < .001) but similar for those with versus without previous treatment (81.7% vs 82.3%, respectively; P = .848). A total of 443 (76.2% of 581) lesions met criteria for curative resection. Median ESD time was 1.0 (range, 0.1-4.5) hour. Median dissection speed was 17.1 (interquartile range, 5.3-29.8) cm2/h. Related serious adverse events were reported in 15 (2.6%) patients, including delayed hemorrhage (1.9%), perforation (0.5%), or postpolypectomy syndrome (0.2%). CONCLUSION: A newly developed through-the-needle injection-capable ESD knife showed a good success rate and excellent safety at U.S. CENTERS: (Clinical trial registration number: NCT04580940.).

Impact and determinants of door in-door out time for stroke thrombectomy transfers in a large hub-and-spoke network.

INTRODUCTION: The mantra "time is brain" cannot be overstated for patients suffering from acute ischemic stroke. This is especially true for those with large vessel occlusions (LVOs) requiring transfer to an endovascular thrombectomy (EVT) capable center. We sought to evaluate the spoke hospital door in-door out (DIDO) times for patients transferred to our hub center for EVT. METHODS: Individuals who first presented with LVO to a spoke hospital and were then transferred to the hub for EVT were retrospectively identified from a prospectively maintained database from January 2019 to November 2022. DIDO was defined as the time between spoke hospital door in arrival and door out exit. Baseline characteristics, treatments, and outcomes were compared, dichotomizing DIDO at 90 minutes based in the American Heart Association goal for DIDO ≤90 minutes for 50% of transfers. Multivariable regression analyses were performed for determinants of the 90-day ordinal modified Rankin Scale (mRS) and DIDO. RESULTS: We identified 194 patients transferred for EVT with available DIDO. The median age was 67 years (IQR 57-80), and 46% were female. The median National Institutes of Health Stroke Scale (NIHSS) was 16 (10-20), 50% were treated with intravenous thrombolysis at a spoke, and TICI 2B-3 reperfusion was achieved in 87% at the hub. The median DIDO was 120 minutes (97-149), with DIDO ≤90 minutes achieved in 18%. DIDO was a significant determinant of 90-day ordinal mRS (B = 0.007, 95% CI = 0.001-0.012, p = 0.013), even when accounting for the last known well-to-spoke door in, spoke door out-to-hub arrival, hub arrival-to-puncture, puncture-to-first pass, age, NIHSS, intravenous thrombolysis, TICI 2B-3, and symptomatic intracranial hemorrhage. Importantly, determinants of DIDO included Black race or Hispanic ethnicity (B = 0.918, 95% CI = 0.010-1.826, p = 0.048), atrial fibrillation or heart failure (B = 0.793, 95% CI = 0.257-1.329, p = 0.004), and basilar LVO location (B = 2.528, 95% CI = 1.154-3.901, p < 0.001). CONCLUSION: Spoke DIDO was the most important period of time for long-term outcomes of LVO stroke patients treated with EVT. Targets were identified to reduce DIDO and improve patient outcomes.

Large-Scale Culture and Plasmid Preparation Procedure for Low-Yield Bacmids Containing Full-Length SARS-CoV-2 cDNAs.

Reverse genetic methods to manipulate viral genomes are key tools in modern virological experimentation. They allow for the generation of reporter virus genomes to simplify the assessment of virus growth and for the analysis of the impact of specific mutations in the genome on virus phenotypes. For SARS-CoV-2, reverse genetic systems are complicated by the large size of the viral genome and the instability of certain genomic sections in bacteria requiring the use of low-copy number bacterial artificial chromosome plasmids (bacmids). However, even with the use of bacmids, faithfully amplifying SARS-CoV-2 bacmids is often challenging. In this chapter, we describe a detailed protocol to grow SARS-CoV-2 bacmids and highlight the challenges and optimal techniques to produce large quantities of SARS-CoV-2 bacmids that are free of deletions and mutations. Overall, this chapter has recapitulated an overview of the maxi-preparation procedure for large unstable bacmids like SARS-CoV-2 to facilitate downstream applications.

Associations between periodontitis and serum anti-malondialdehyde-acetaldehyde antibody concentrations in rheumatoid arthritis: A case-control study.

BACKGROUND: Malondialdehyde-acetaldehyde (MAA) adducts lead to generation of anti-MAA autoantibodies and have been independently identified in inflamed periodontal and rheumatoid arthritis (RA) tissues. This study evaluates serum samples from RA cases and osteoarthritis (OA) controls to quantify associations between periodontal clinical measures, alveolar bone loss (ABL), and anti-Porphyromonas gingivalis, anti-Prevotella intermedia, and anti-Fusobacterium nucleatum antibody concentrations with anti-MAA antibody concentrations. METHODS: Participants (n = 284 RA cases, n = 330 OA controls) underwent periodontal clinical assessments and ABL measurements. Serum immunoglobulin (Ig) A, IgG, and IgM anti-MAA and serum IgG antibacterial antibody concentrations were quantified by enzyme-linked immunosorbent assay (ELISA). Analyses utilized simple linear regression and multivariable adjusted models. RESULTS: No significant associations of periodontal clinical measures with serum anti-MAA were found. Moderate (p = 0.038 and p = 0.036, respectively) and high ABL (p = 0.012 and p = 0.014, respectively) in RA cases (but not in OA) were positively associated with IgG and IgM anti-MAA. Anti-P. gingivalis and anti-P. intermedia antibody concentrations were positively associated with IgA (p = 0.001 for both), IgG (p = 0.007 and p = 0.034, respectively), and IgM anti-MAA antibody concentrations (p < 0.001 and p = 0.020, respectively), while anti-F. nucleatum was positively associated with IgG anti-MAA (p = 0.042), findings that were similar across groups. CONCLUSIONS: A positive association was demonstrated between ABL and serum IgG and IgM anti-MAA antibody concentrations that was unique to RA and not observed in OA. Serum anti-P. gingivalis, anti-P. intermedia, and anti-F. nucleatum antibody concentrations displayed significant associations with anti-MAA antibody in both groups. These findings suggest MAA may play a role in the interrelationship between the periodontium and RA.

Genetic variability of Aedes aegypti (Diptera: Culicidae) in El Salvador and Honduras: presence of a widespread haplotype and implications for mosquito control.

BACKGROUND: This study examined population genetics of Aedes aegypti in El Salvador and Honduras, two adjacent countries in Central America. Aedes aegypti is associated with yellow fever, dengue, chikungunya, and Zika. Each year, thousands of cases of dengue are typically reported in El Salvador and Honduras. METHODS: In El Salvador, collections were obtained from five Departments. In Honduras, samples were obtained from six municipalities in four Departments. Mitochondrial DNA cytochrome oxidase I (COI) was sequenced, and consensus sequences were combined with available sequences from El Salvador to determine haplotype number, haplotype diversity, nucleotide diversity, and Tajima's D. A haplotype network was produced to examine the relationship between genotypes. RESULTS: In El Salvador, there were 17 haplotypes, while in Honduras there were 4 haplotypes. In both El Salvador and Honduras, Haplotype 1 is most abundant and widespread. In El Salvador, haplotype H2 was also widespread in 10 of 11 sampled municipalities, but it was not present in Honduras. The capital of El Salvador (San Salvador) and the eastern region of ES had the highest haplotype diversity of regions sampled. CONCLUSIONS: Haplotype 1 and H2 each belong to different phylogenetic lineages of Ae. aegypti. The most geographically widespread haplotype (H1) may have been present the longest and could be a remnant from previous eradication programs. These data may contribute to future control programs for Ae. aegypti in the two countries.

Births: Final Data for 2022.

Objectives- This report presents 2022 data on U.S. births by selected characteristics. Trends in fertility patterns and maternal and infant characteristics are described. Methods-Descriptive tabulations based on birth certificates of the 3.67 million births registered in 2022 are shown by maternal age, live-birth order, race and Hispanic origin, marital status, tobacco use, prenatal care, source of payment for the delivery, method of delivery, gestational age, birthweight, and plurality. Selected data by mother's state of residence and birth rates also are shown. Trends for 2010 to 2022 are presented for selected items, and by race and Hispanic origin for 2016-2022. Results-A total of 3,667,758 births occurred in the United States in 2022, essentially unchanged from 2021. The general fertility rate declined 1% from 2021 to 56.0 births per 1,000 females ages 15-44 in 2022. The birth rate for females ages 15-19 declined 2% from 2021 to 2022; birth rates fell 7% for women ages 20-24, rose 1% to 5% for women ages 25-29 and 35-44, and rose 12% for women ages 45-49 (the first increase since 2016). The total fertility rate declined less than 1% to 1,656.5 births per 1,000 women in 2022. Birth rates declined for unmarried women but increased for married women from 2021 to 2022. Prenatal care beginning in the first trimester declined to 77.0% in 2022; the percentage of women who smoked during pregnancy declined to 3.7%. The cesarean delivery rate was unchanged in 2022 (32.1%); Medicaid was the source of payment for 41.3% of births. The preterm birth rate declined 1% to 10.38%; the low birthweight rate rose 1% to 8.60%. The twin birth rate was unchanged in 2022 (31.2 per 1,000 births); the 2% decrease in the triplet and higher-order multiple birth rate.

Impact of the Breast Cancer Index for Extended Endocrine Decision-Making: First Results of the Prospective BCI Registry Study.

BACKGROUND: The Breast Cancer Index (BCI) test assay provides an individualized risk of late distant recurrence (5-10 years) and predicts the likelihood of benefitting from extended endocrine therapy (EET) in hormone receptor-positive early-stage breast cancer. This analysis aimed to assess the impact of BCI on EET decision-making in current clinical practice. METHODS: The BCI Registry study evaluates long-term outcomes, decision impact, and medication adherence in patients receiving BCI testing as part of routine clinical care. Physicians and patients completed pre-BCI and post-BCI test questionnaires to assess a range of questions, including physician decision-making and confidence regarding EET; patient preferences and concerns about the cost, side effects, drug safety, and benefit of EET; and patient satisfaction regarding treatment recommendations. Pre-BCI and post-BCI test responses were compared using McNemar's test and Wilcoxon signed rank test. RESULTS: Pre-BCI and post-BCI questionnaires were completed for 843 physicians and 823 patients. The mean age at enrollment was 65 years, and 88.4% of patients were postmenopausal. Of the tumors, 74.7% were T1, 53.4% were grade 2, 76.0% were N0, and 13.8% were HER2-positive. Following BCI testing, physicians changed EET recommendations in 40.1% of patients (P<.0001), and 45.1% of patients changed their preferences for EET (P<.0001). In addition, 38.8% of physicians felt more confident in their recommendation (P<.0001), and 41.4% of patients felt more comfortable with their EET decision (P<.0001). Compared with baseline, significantly more patients were less concerned about the cost (20.9%; P<.0001), drug safety (25.4%; P=.0014), and benefit of EET (29.3%; P=.0002). CONCLUSIONS: This analysis in a large patient cohort of the BCI Registry confirms and extends previous findings on the significant decision-making impact of BCI on EET. Incorporating BCI into clinical practice resulted in changes in physician recommendations, increased physician confidence, improved patient satisfaction, and reduced patient concerns regarding the cost, drug safety, and benefit of EET.

Targeting HER2/HER3 co-mutations in metastatic breast cancer: Case reports of exceptional responders to trastuzumab and pertuzumab therapy.

BACKGROUND: Overexpression of HER2 plays an important role in cancer progression and is the target of multiple therapies in HER2-positive breast cancer. Recent studies have also highlighted the presence of activating mutations in HER2, and HER3 that are predicted to enhance HER2 downstream pathway activation in a HER2-dependent manner. METHODS: In this report, we present two exceptional responses in hormone receptor-positive, HER2-nonamplified, HER2/HER3 co-mutated metastatic breast cancer patients who were treated with the anti-HER2-directed monoclonal antibodies, trastuzumab and pertuzumab. RESULTS: Both patients acheived exceptional responses to treatment, suggesting that combined trastuzumab, pertuzumab, and endocrine therapy could be a highly effective therapy for these patients and our observations could help prioritize trastuzumab deruxtecan as an early therapeutic choice for patients whose cancers have activating mutations in HER2.

Too loud to hear myself think: deleterious effects of noise in the operating room.

Noise is part of daily life in the operating room, and too often is viewed as a necessary evil. However, much of the noise in operating rooms (ORs) is unnecessary, such as extraneous conversations and music, and could be reduced. At the least, noise is known to increase staff stress and to hamper effective communication; at the worst, it adversely affects patient outcomes. Every member of the OR team should be cognisant of this and work to reduce unnecessary noise.

Activity and safety of enobosarm, a novel, oral, selective androgen receptor modulator, in androgen receptor-positive, oestrogen receptor-positive, and HER2-negative advanced breast cancer (Study G200802): a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial.

BACKGROUND: The androgen receptor is a tumour suppressor in oestrogen receptor-positive breast cancer. The activity and safety of enobosarm, an oral selective androgen receptor modulator, was evaluated in women with oestrogen receptor (ER)-positive, HER2-negative, and androgen receptor (AR)-positive disease. METHODS: Women who were postmenopausal (aged ≥18 years) with previously treated ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled in a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial done at 35 cancer treatment centres in nine countries. Participants were stratified on the setting of immediately preceding endocrine therapy and the presence of bone-only metastasis and randomly assigned (1:1) to 9 mg or 18 mg oral enobosarm daily using an interactive web response system. The primary endpoint was clinical benefit rate at 24 weeks in those with centrally confirmed AR-positive disease (ie, the evaluable population). This trial is registered with ClinicalTrials.gov (NCT02463032). FINDINGS: Between Sept 10, 2015, and Nov 28, 2017, 136 (79%) of 172 patients deemed eligible were randomly assigned to 9 mg (n=72) or 18 mg (n=64) oral enobosarm daily. Of these 136 patients, 102 (75%) patients formed the evaluable population (9 mg, n=50; 18 mg, n=52). The median age was 60·5 years (IQR 52·3-69·3) in the 9 mg group and 62·5 years (54·0-69·3) in the 18 mg group. The median follow-up was 7·5 months (IQR 2·9-14·1). At 24 weeks, 16 (32%, 95% CI 20-47) of 50 in the 9 mg group and 15 (29%, 17-43) of 52 in the 18 mg group had clinical benefit. Six (8%) of 75 patients who received 9 mg and ten (16%) of 61 patients who received 18 mg had grade 3 or grade 4 drug-related adverse events, most frequently increased hepatic transaminases (three [4%] of 75 in the 9 mg group and two [3%] of 61 in the 18 mg group), hypercalcaemia (two [3%] and two [3%]), and fatigue (one [1%] and two [3%]). Four deaths (one in the 9 mg group and three in the 18 mg group) were deemed unrelated to the study drug. INTERPRETATION: Enobosarm has anti-tumour activity in patients with ER-positive, HER2-negative advanced breast cancer, showing that AR activation can result in clinical benefit, supporting further clinical investigation of selective AR activation strategies for the treatment of AR-positive, ER-positive, HER2-negative advanced breast cancer. FUNDING: GTx.

Shifts in the Distribution of Births by Gestational Age: United States, 2014-2022.

Objectives-This report presents changes in the distribution of singleton births by gestational age in the United States for 2014-2022, by maternal age and race and Hispanic origin. Methods-Data are based on all birth certificates for singleton births registered in the United States from 2014 to 2022. Gestational age is measured in completed weeks using the obstetric estimate and categorized as early preterm (less than 34 weeks), late preterm (34-36 weeks), total preterm (less than 37 weeks), early term (37-38 weeks), full term (39-40 weeks), and late- and post-term (41 and later weeks). Data are shown by maternal age and race and Hispanic origin. Single weeks of gestation at term (37-41 weeks) are also examined. Results-Despite some fluctuation in most gestational age categories during the pandemic years of 2020-2022, trends from 2014 to 2022 demonstrate a shift towards shorter gestational ages. Preterm and early-term birth rates rose from 2014 to 2022 (by 12% and 20%, respectively), while full-term and lateand post-term births declined (by 6% and 28%, respectively). Similar shifts for each gestational age category were seen across maternal age and race and Hispanic-origin groups. By single week of gestation at term, the largest change was for births at 37 weeks (an increase of 42%).

Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]).

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The primary joint efficacy analysis of the Anthracyclines in Early Breast Cancer (ABC) trials reported in 2017 failed to demonstrate nonanthracycline adjuvant therapy was noninferior to anthracycline-based regimens in high-risk, early breast cancer. Full analyses of the studies had proceeded when the prespecified futility boundary was crossed at a planned futility analysis for the ability to demonstrate noninferiority of a nonanthracycline regimen with continued follow-up. These results were presented with 3.3 years of median follow-up. This manuscript reports results of the final analyses of the study efficacy end points conducted with 6.9 years of median follow-up. Long-term analysis of invasive disease-free survival (IDFS), the primary end point of the ABC trials, remains consistent with the original results, as noninferiority of the nonanthracycline regimens could not be declared on the basis of the original criteria. The secondary end point of recurrence-free interval, which excluded deaths not due to breast cancer as events, favored anthracycline-based regimens, and tests for heterogeneity were significant for hormone receptor status (P = .02) favoring anthracycline regimens for the hormone receptor-negative cohorts. There was no difference in overall survival, and review of the type of IDFS events in the groups suggested reductions in cancer recurrences achieved with anthracycline regimens were offset by late leukemias and deaths unrelated to breast cancer.

Synergistic interaction of polymyxin B with carvacrol: antimicrobial strategy against polymyxin-resistant Klebsiella pneumoniae.

Objective: The antimicrobial activities of the synergistic combination of carvacrol and polymyxin B against polymyxin-resistant Klebsiella pneumoniae were evaluated. Methods: The methods employed checkerboard assays to investigate synergism, biofilm inhibition assessment and membrane integrity assay. In addition, the study included in vivo evaluation using a mouse infection model. Results: The checkerboard method evaluated 48 combinations, with 23 indicating synergistic action. Among these, carvacrol 10 mg/kg plus polymyxin B 2 mg/kg exhibited in vivo antimicrobial activity in a mouse model of infection, resulting in increased survival and a significant decrease in bacterial load in the blood. Conclusion: Polymyxin in synergy with carvacrol represents a promising alternative to be explored in the development of new antimicrobials.

In this study, we wanted to find a new way to fight a bacteria called Klebsiella pneumoniae, which is not easily killed by medication. We mixed two drugs, carvacrol and polymyxin B, to see if they would work together to fight the bacteria. We found that the mixed treatment helped to kill the bacteria. We also tried this mixed treatment in sick mice, and they got better. Our study shows that this mixed treatment might be a new way to fight bacteria that are hard to kill with regular drugs. Next, we hope to learn more about how it works.

A Multi-Institutional Description of Processes and Outcomes of Postbaccalaureate Research Education Programs in the Mid-Atlantic Region.

ABSTRACT: Outcome data from 6 National Institutes of Health-funded Postbaccalaureate Research Education Programs (PREPs) in the Mid-Atlantic region were combined to give a multi-institutional perspective on their scholars' characteristics and progress through biomedical research training. The institutions hosting these programs were Johns Hopkins University School of Medicine, the Medical University of South Carolina, the University of Maryland School of Medicine, the University of North Carolina at Chapel Hill, Virginia Commonwealth University, and Virginia Polytechnic Institute and State University. The authors summarize the institutional pathways, demographics, undergraduate institutions, and graduate institutions for a total of 384 PREP scholars who completed the programs by June 2021. A total of 228 (59.4%) of these PREP scholars identified as Black or African American, 116 (30.2%) as Hispanic or Latinx, and 269 (70.0%) as female. The authors found that 376 of 384 scholars (97.9%) who started PREP finished their program, 319 of 376 (84.8%) who finished PREP matriculated into PhD or MD/PhD programs, and 284 of 319 (89.0%) who matriculated have obtained their PhD or are successfully making progress toward their PhD.