Correlating maternal and cord-blood inflammatory markers and BDNF with human fetal brain activity recorded by magnetoencephalography: An exploratory study.

Background: During gestation, the brain development of the fetus is affected by many biological markers, where inflammatory processes and neurotrophic factors have been of particular interest in the past decade. Aim: This exploratory study is the first attempt to explore the relationships between biomarker levels in maternal and cord-blood samples and human fetal brain activity measured with non-invasive fetal magnetoencephalography (fMEG). Method: Twenty-three women were enrolled in this study for collection of maternal serum and fMEG tracings immediately prior to their scheduled cesarean delivery. Twelve of these women had a preexisting diabetic condition. At the time of delivery, umbilical cord blood was also collected. Biomarker levels from both maternal and cord blood were measured and subsequently analyzed for correlations with fetal brain activity in four frequency bands extracted from fMEG power spectral densities. Results: Relative power in the delta, alpha, and beta frequency bands exhibited moderate-sized correlations with maternal BDNF and cord-blood CRP levels before and after adjusting for confounding diabetic status. These correlations were negative for the delta band, and positive for the alpha and beta bands. Maternal CRP and cord-blood BDNF and IL-6 exhibited negligible correlations with relative power in all four bands. Diabetes did not appear to be a strong confounding factor affecting the studied biomarkers. Conclusions: Maternal BDNF levels and cord-blood CRP levels appear to have a direct correlation to fetal brain activity. Our findings indicate the potential use of these biomarkers in conjunction with fetal brain electrophysiology to track fetal neurodevelopment.

Spinal height for growth guidance treatment in early onset idiopathic scoliosis: analysis through final surgical treatment.

BACKGROUND: The growth guidance (GG) method for treatment of early onset scoliosis has as its primary goal the restoration of apical spinal alignment, facilitating normal spinal growth to achieve a suitable adult thoracic height. PURPOSE: To evaluate whether GG surgical treatment achieves comparable thoracic and spinal height to distraction-based treatment (DBT) in idiopathic early onset scoliosis (I-EOS) patients. We hypothesized that GG would prove superior to DBT at the time of definitive fusion surgery. METHODS: All I-EOS patients who underwent GG at a single center were reviewed. T1-L1 and T1-S1 heights were measured using the traditional coronal method as well as the Halifax sagittal spinal length (SSL) technique. The same measurements were obtained from a comparable control group obtained from a multi-center pediatric early onset scoliosis database who underwent treatment with traditional growing rods (TGR) or magnetically controlled growing rods (MCGR). RESULTS: Of the I-EOS patients who underwent GG 2004-2019, 15 patients underwent final fusion after GG completion, with a mean 5.5 years of GG treatment prior to fusion (range 2.0-11.4 years). Mean age at GG implantation was 8.4 years (range 2.0-11.7 years); 7 were male and 8 female. GG patients experienced a mean coronal thoracic height increase of 6.2 cm during treatment through final fusion, and a mean coronal spinal height increase of 8.8 cm. At the time of final fusion, GG patients achieved greater significant mean increases than DBT patients by 2.9 cm in coronal thoracic height (p = 0.0023), 4.5 cm in coronal spinal height (p = 0.001), and 4.0 cm in SSL spinal height (p = 0.01). No GG patient concluded treatment with a thoracic height less than 18 cm in either coronal or sagittal plane. CONCLUSIONS: Not only did 100% of GG patients reach minimum thoracic height of 18 cm at time of final fusion, but GG also proved to be superior to distraction-based constructs in a comparison cohort on 3 of 4 spinal elongation measures. LEVEL OF EVIDENCE: 3.

Fetal magnetocardiographic recordings with a prototype bed-based array system of optically-pumped magnetometers.

OBJECTIVE: To record and extract features of fetal cardiac activities with a semi-rigid prototype optically-pumped magnetometers (OPM) sensor array. METHODS: Fetal magnetocardiography (fMCG) data were collected from 15 pregnant women between 28 and 40 weeks gestation. Mothers were lying flat in a customized bed with sensors touching their abdomen from below using a prototype grid. fMCG was extracted to perform standard fetal heart rate variability (FHRV) analysis. RESULTS: fMCG was observed in 13 of the 15 pregnant women. OPM FHRV indicators were in the range of previous SQUID studies. CONCLUSION: Semi-rigid prototype OPM system has the ability to record quality fMCG. fMCG is capable of identifying lethal cardiac rhythm disturbances in the fetus. Our novel application of OPM technology may lower costs and increase maternal comfort, thus expanding fMCG's generalizability.

Randomized Phase II Trial of Imiquimod with or without 9-Valent HPV Vaccine versus Observation in Patients with High-grade Pre-neoplastic Cervical Lesions (NCT02864147).

PURPOSE: We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator versus imiquimod plus a 9-valent human papillomavirus (HPV) vaccine (9vHPV) versus clinical surveillance in cervical intraepithelial neoplasia (CIN2/3) patients. PATIENTS AND METHODS: We randomly allocated 133 patients with untreated CIN2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (Arm B) or imiquimod plus a 9vHPV (Arm C) versus clinical surveillance (Arm A). The main outcome was efficacy, defined as histologic regression to CIN1 or less. Secondary outcomes were HPV clearance and tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and posttreatment by flow cytometry among study arms. RESULTS: Of the 114 evaluable patients 77% and 23% harbored CIN2 and CIN3, respectively. Regression to CIN1 or less was observed in 95% of patients in the imiquimod group (Arm B) compared with 79% in the control/surveillance (Arm A); P = 0.043 and 84% in the imiquimod+9vHPV group (Arm C; P = 0.384 vs. Arm A). Neither of the treatment-arm differences from Arm A reached the prespecified α = 0.025 significance level. No significant differences were noted in the secondary outcome of rate of HPV clearance. The number of tissue-resident memory CD4/CD8 T cells in cytobrush samples demonstrated a >5-fold increase in Arm B/imiquimod when compared with Arm A/surveillance (P < 0.01). In contrast, there was no significant difference in T-cell responses among participants in Arm C when compared with Arm A. Imiquimod treatment was well tolerated. CONCLUSIONS: Although imiquimod induced a higher regression to CIN1 or less and significant increases in CD4/CD8 T cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trials with imiquimod targeting CIN3 patients are warranted.

Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix.

High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in PIK3CA, KMT2D/MLL2, K-RAS, ARID1A, NOTCH2, and RPL10. The top mutated genes included RB1, ARID1A, PTEN, KMT2D/MLL2, and WDFY3, a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36.21/5q31.3/6p22.2/9q21.11/11p15.5). Also, gene fusions affecting the ACLY-CRHR1 and PVT1-MYC genes were identified in one of the eight samples subjected to RNA sequencing. To resolve evolutionary history, multiregion WES in NETc admixed with adenocarcinoma cells was performed (i.e., mixed-NETc). Phylogenetic analysis of mixed-NETc demonstrated that adenocarcinoma and neuroendocrine elements derive from a common precursor with mutations typical of adenocarcinomas. Over one-third (22/64) of NETc demonstrated a mutator phenotype of C > T at CpG consistent with deficiencies in MBD4, a member of the base excision repair (BER) pathway. Mutations in the PI3K/AMPK pathways were identified in 49/64 samples. We used two patient-derived-xenografts (PDX) (i.e., NET19 and NET21) to evaluate the activity of pan-HER (afatinib), PIK3CA (copanlisib), and ATR (elimusertib) inhibitors, alone and in combination. PDXs harboring alterations in the ERBB2/PI3K/AKT/mTOR/ATR pathway were sensitive to afatinib, copanlisib, and elimusertib (P < 0.001 vs. controls). However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies.

Successful Transition to Same Calendar Day Discharge in Total Joint Arthroplasty at an Academic Center.

Background: There has been a shift toward same-day discharge (SDD) in total joint arthroplasty (TJA) in recent years. Our clinical standard had been next-day discharge, but the COVID pandemic led to a hospital bed shortage, causing us to shift to SDD directly from the Post-Anesthesia Care Unit (PACU). The aim of our project was to investigate if the SDD protocol was successful and if it changed complications or 90-day readmission rates. Our secondary aim was to investigate if the protocol created disparities in patient selection. Methods: A retrospective review compared the first 100 patients intended to discharge from PACU to the 100 patients prior to the SDD protocol undergoing elective primary TJA procedures at our academic institution from September 1, 2020, to March 23, 2021. The SDD protocol started on November 19, 2020. Results: During this SDD period, 98% (98/100) of patients were successfully discharged from the PACU. The 90-day readmission rate changed from 0% to 2% (P = .4975), and the overall complication rate changed from 2% to 5% (P = .4448). Most complications were manipulation under anesthesia to improve range of motion. Manipulations under anesthesia changed from 1% to 4% (P = .3687). Conclusions: The transition to same SDD in TJA at our academic institution was successfully implemented without markedly increasing complications, readmissions, or changing patient selection. The COVID-19 pandemic likely influenced the recovery of patients before and after the protocol. Future studies are needed to validate this data during the post-COVID era.

A Risk Stratification System in Myeloma Patients with Autologous Stem Cell Transplantation.

Autologous stem cell transplantation (ASCT) has been a mainstay in myeloma treatment for over three decades, but patient prognosis post-ASCT varies significantly. In a retrospective study of 5259 patients with multiple myeloma (MM) at the University of Arkansas for Medical Sciences undergoing ASCT with a median 57-month follow-up, we divided the dataset into training (70%) and validation (30%) subsets. Employing univariable and multivariable Cox analyses, we systematically assessed 29 clinical variables, identifying crucial adverse prognostic factors, such as extended duration between MM diagnosis and ASCT, elevated serum ferritin, and reduced transferrin levels. These factors could enhance existing prognostic models. Additionally, we pinpointed significant poor prognosis markers like high serum calcium and low platelet counts, though they are applicable to a smaller patient population. Utilizing seven easily accessible high-risk variables, we devised a four-stage system (ATM4S) with primary stage borders determined through K-adaptive partitioning. This staging system underwent validation in both the training dataset and an independent cohort of 514 ASCT-treated MM patients from the University of Iowa. We also explored cytogenetic risk factors within this staging system, emphasizing its potential clinical utility for refining prognostic assessments and guiding personalized treatment approaches.

Correlation of fetal heart rate dynamics to inflammatory markers and brain-derived neurotrophic factor during pregnancy.

OBJECTIVES: This study aims to show the relation between biomarkers in maternal and cord-blood samples and fetal heart rate variability (fHRV) metrics through a non-invasive fetal magnetocardiography (fMCG) technique. METHODS: Twenty-three women were enrolled for collection of maternal serum and fMCG tracings immediately prior to their scheduled cesarean delivery. The umbilical cord blood was collected for measurement of biomarker levels. The fMCG metrics were then correlated to the biomarker levels from the maternal serum and cord blood. RESULTS: Brain-derived neurotrophic factor (BDNF) had a moderate correlation with fetal parasympathetic activity (0.416) and fetal sympathovagal ratios (-0.309; -0.356). Interleukin (IL)-6 also had moderate-sized correlations but with an inverse relationship as compared to BDNF. These correlations were primarily in cord-blood samples and not in the maternal blood. CONCLUSIONS: In this small sample-sized exploratory study, we observed a moderate correlation between fHRV and cord-blood BDNF and IL-6 immediately preceding scheduled cesarean delivery at term. These findings need to be validated in a larger population.

Hospital-Wide Adherence to Postsurgical Opioid Prescribing Guidelines: A Retrospective Cohort Study.

INTRODUCTION: Lowering opioid prescription doses and quantity decreases the risk of chronic opioid usage. A tool was inserted into the brief operative note for the surgeon to assess the severity of pain associated with the procedure. We studied surgeon adherence to current opioid-prescribing recommendations. METHODS: Retrospective cohort study with 5486 patients were included in the study population. Each patient's prescription was scored yes or no for adherence on total morphine milligram equivalents (MMEs) and days prescribed with the selection in the brief operative note. The entire study population was tested for an increase from the null-hypothesis "benchmark" value of 75% using a one-sided exact binomial test of a single proportion with P < 0.05. This procedure was repeated for subgroups, with P < 0.01. RESULTS: Adherence to guidelines was higher than the 75% benchmark for "total MMEs prescribed" (79.5%; P < 0.001), but lower for "number of days prescribed" (63.5%; P > 0.999). Surgeries with severe predicted pain showed the highest adherence toward total MMEs prescribed at 87.1%, followed by moderate (80.5%) and mild (74.5%). Severe cases also showed the highest adherence in number of days prescribed (92.4%). Adherence to total MMEs prescribed was highest among attending physicians (88.1%) and lowest among residents/fellows (76.6%). CONCLUSIONS: Adherence to current guidelines was 79.5% for MMEs prescribed but only 63.5% for days prescribed. Compliance with guidelines was better for severe procedures than mild or moderate. Differences were seen across surgical departments. While an improvement from previous reports, further improvement is needed to reduce the number of days of opioids prescribed and increase compliance with recommended guidelines.

Do Quality Measures or Hospital Characteristics Predict Readmission Penalties for Hip and Knee Arthroplasty?

BACKGROUND: Quality rating systems exist to grade the value of care provided by hospitals, but the extent to which these rating systems correlate with patient outcomes is unclear. The association of quality rating systems and hospital characteristics with excess readmission penalties for total hip arthroplasty (THA) and total knee arthroplasty (TKA) was studied. METHODS: The fiscal year 2022 Inpatient Prospective Payment System final rule was used to identify 2,286 hospitals subject to the Hospital Readmissions Reduction Program. Overall, 6 hospital quality rating systems and 5 hospital characteristics were obtained. These factors were analyzed to determine the effect on hospital penalties for THA and TKA excess readmissions. RESULTS: Hospitals that achieved a higher Medicare Overall Hospital Quality Star Rating demonstrated a significantly lower likelihood of receiving THA and TKA readmission penalties (Cramer's V = 0.236 and Rp = -0.233; P < .001 for both). Hospitals ranked among the US News & World Report's top 50 best hospitals for orthopaedics were significantly less likely to be penalized (V = 0.042; P = .043). The remaining 4 quality rating systems were not associated with readmission penalties. Penalization was more likely for hospitals with fewer THA and TKA discharges (Rp = -0.142; P < .001), medium-sized institutions (100 to 499 beds; V = 0.075; P = .002), teaching hospitals (V = 0.049; P = .019), and safety net hospitals (V = 0.043; P = .039). Penalization was less likely for West and Midwest hospitals (V = 0.112; P < .001). CONCLUSIONS: A higher Overall Hospital Quality Star Rating and recognition among the US News & World Report's top 50 orthopaedic hospitals were associated with a reduced likelihood of THA and TKA readmission penalties. The other 4 widely accepted quality rating systems did not correlate with readmission penalties. Teaching and safety net hospitals may be biased toward higher readmission rates.

Active Surveillance of Powassan Virus in Massachusetts Ixodes scapularis Ticks, Comparing Detection Using a New Triplex Real-Time PCR Assay with a Luminex Vector-Borne Panel.

Powassan virus is an emerging tick-borne pathogen capable of causing severe neuroinvasive disease. As the incidence of human Powassan virus grows both in magnitude and geographical range, the development of sensitive detection methods for diagnostics and surveillance is critical. In this study, a Taqman-based triplex real-time PCR assay was developed for the simultaneous and quantitative detection of Powassan virus and Powassan virus lineage II (deer tick virus) in Ixodes scapularis ticks. An exon-exon junction internal control was built-in to allow for accurate detection of RNA quality and the failure of RNA extraction. The newly developed assay was also applied to survey deer tick virus in tick populations at 13 sites on Cape Cod and Martha's Vineyard Island in Massachusetts. The assay's performance was compared with the Luminex xMAP MultiFLEX Vector-borne Panel 2. The results suggested that the real-time PCR method was more sensitive. Powassan virus infection rates among ticks collected from these highly endemic tick areas ranged from 0.0 to 10.4%, highlighting the fine-scale geographic variations in deer tick virus presence in this region. Looking forward, our PCR assay could be adopted in other Powassan virus surveillance systems.

Does the type of lower extremity fracture affect long-term opioid usage? A meta-analysis.

INTRODUCTION:  Patients recovering from musculoskeletal trauma have a heightened risk of opioid dependence and misuse, as these medications are typically required for pain management. The purpose of this meta-analysis was to examine the association between fracture type and chronic opioid use following fracture fixation in patients who sustain lower extremity trauma. MATERIALS AND METHODS: A meta-analysis was performed using PubMed and Web of Science to identify articles reporting chronic opioid use in patients recovering from surgery for lower extremity fractures. 732 articles were identified using keyword and MeSH search functions, and 9 met selection criteria. Studies were included in the final analysis if they reported the number of patients who remained on opioids 6 months after surgery for a specific lower extremity fracture (chronic usage). Logistic regressions and descriptive analyses were performed to determine the rate of chronic opioid use within each fracture type and if age, year, country of origin of study, or pre-admission opioid use influenced chronic opioid use following surgery. RESULTS: Bicondylar and unicondylar tibial-plateau fractures had the largest percentage of patients that become chronic opioid users (29.7-35.2%), followed by hip (27.8%), ankle (19.7%), femoral-shaft (18.5%), pilon (17.2%), tibial-shaft (13.8%), and simple ankle fractures (2.8-4.7%).Most opioid-naive samples had significantly lower rates of chronic opioid use after surgery (2-9%, 95% CI) when compared to samples that allowed pre-admission opioid use (13-50%, 95% CI). There were no significant associations between post-operative chronic opioid use and age, year, or country of origin of study. CONCLUSIONS:  Patients with lower extremity fractures have substantial risk of becoming chronic opioid users. Even the lowest rates of chronic opioid use identified in this meta-analysis are higher than those in the general population. It is important that orthopedic surgeons tailor pain-management protocols to decrease opioid usage after lower extremity trauma.

Bispecific BCMA/CD24 CAR-T cells control multiple myeloma growth.

Anti-multiple myeloma B cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapies represent a promising treatment strategy with high response rates in myeloma. However, durable cures following anti-BCMA CAR-T cell treatment of myeloma are rare. One potential reason is that a small subset of minimal residual myeloma cells seeds relapse. Residual myeloma cells following BCMA-CAR-T-mediated treatment show less-differentiated features and express stem-like genes, including CD24. CD24-positive myeloma cells represent a large fraction of residual myeloma cells after BCMA-CAR-T therapy. In this work, we develop CD24-CAR-T cells and test their ability to eliminate myeloma cells. We find that CD24-CAR-T cells block the CD24-Siglec-10 pathway, thereby enhancing macrophage phagocytic clearance of myeloma cells. Additionally, CD24-CAR-T cells polarize macrophages to a M1-like phenotype. A dual-targeted BCMA-CD24-CAR-T exhibits improved efficacy compared to monospecific BCMA-CAR-T-cell therapy. This work presents an immunotherapeutic approach that targets myeloma cells and promotes tumor cell clearance by macrophages.

Increased von Willebrand and Factor VIII plasma levels in gynecologic patients with Post-Acute-COVID-Sequela (PASC)/Long COVID.

Up to 30 % of COVID-infected patients may develop post-acute sequelae of COVID-19 (PASC), also known as Long COVID (LC), a syndrome characterized by a variety of debilitating symptoms lasting for more than 3 months after the acute infection. While the pathophysiological mechanisms behind PASC/LC are not completely understood, growing evidence suggests that an important component of this syndrome may be related to persistent microvascular inflammation causing clumping/clotting of red blood cells and platelets and thrombotic complications. We retrospectively evaluated the plasma levels of von Willebrand factor (VWF), Factor VIII and D-dimer in 10 gynecologic patients (60 % with an endometrial or ovarian cancer diagnosis) affected by PASC/LC vs 5 control patients (60 % harboring endometrial or ovarian tumors). We found elevated VWF and Factor VIII levels in all 10 PASC/LC patients (means of 254 % and 229 %, respectively) vs none of the 5 randomly selected cancer control patients (means of 108 % and 95 %, respectively), p = 0.0046 and p < 0.0001, respectively. In contrast, no significant difference was noted in the levels of D-dimer in PASC/LC. Importantly, abnormally elevated VWF and Factor VIII levels were found to persist for at least 2 years in patients with Long COVID symptoms. VWF and Factor VIII but not D-dimer levels are significantly elevated in the plasma of PASC/LC cancer patients. Abnormally and persistently elevated VWF and Factor VIII levels may represent the results of persistent microvascular damage (i.e., spike-induced endotheliosis) and may be biomarkers of persistent inflammation in gynecologic patients with PASC/LC.

Exploring the Influence of Fetal Sex on Heart Rate Dynamics Using Fetal Magnetocardiographic Recordings.

Fetal sex has been associated with different development trajectories that cause structural and functional differences between the sexes throughout gestation. Fetal magnetocardiography (fMCG) recordings from 123 participants (64 females and 59 males; one recording/participant) from a database consisting of low-risk pregnant women were analyzed to explore and compare fetal development trajectories of both sexes. The gestational age of the recordings ranged from 28 to 38 weeks. Linear metrics in both the time and frequency domains were applied to study fetal heart rate variability (fHRV) measures that reveal the dynamics of short- and long-term variability. Rates of linear change with GA in these metrics were analyzed using general linear model regressions with assessments for significantly different variances and GA regression slopes between the sexes. The fetal sexes were well balanced for GA and sleep state. None of the fHRV measures analyzed exhibited significant variance heterogeneity between the sexes, and none of them exhibited a significant sex-by-GA interaction. The absence of a statistically significant sex-by-GA interaction on all parameters resulted in none of the regression slope estimates being significantly different between the sexes. With high-precision fMCG recordings, we were able to explore the variation in fHRV parameters as it relates to fetal sex. The fMCG-based fHRV parameters did not show any significant difference in rates of change with gestational age between sexes. This study provides a framework for understanding normal development of the fetal autonomic nervous system, especially in the context of fetal sex.

Postoperative Opioid Consumption is Greater after Simultaneous versus Staged Bilateral Total Knee Arthroplasty.

Increased exposure to opioids around total knee arthroplasty (TKA) can lead to a risk of long-term dependence. We hypothesized that performing simultaneous bilateral total knee arthroplasty (simBTKA) over staged surgery (staged bilateral total knee arthroplasty [stgBTKA]) may decrease the total amount of opiates used. We retrospectively reviewed 29 patients who underwent simBTKAs performed between February 2015 and November 2020 and identified 23 that did not use opioids ≤90 days prior to surgery. These were frequency matched for gender and body mass index to 50 stgBTKAs completed within 6 months who also were opioid-free ≤90 days prior to their first surgery. Using our state's prescription database, we reviewed postsurgery opioid refills and morphine milligram equivalents (MMEs) for the two groups and compared their initial MME prescription at discharge and their total MME consumption 6 months postoperatively. Total MME consumption for the stgBTKA group included all prescriptions following the first and 6 months after the second surgery, whereas for the simBTKA group, total consumption included the 6 months after their two same-day surgeries. The simBTKA group had more MMEs prescribed initially (median = 375) than did the stgBTKA group after second surgery (median = 300; p < 0.007), larger postoperative-refill MMEs in the first 30 days (median = 300) than stgBTKA (median = 0; p = 0.221) and increased total MME consumption 6 months after surgery (median = 675) compared with stgBTKA after second surgery (median = 450; p = 0.077). However, both groups had similar monthly consumptions rates, with medians I MMEs/month of 112 for simBTKA versus 96 for stgBTKA (p = 0.585). Our results suggest there is no significant difference in opioid consumption between simBTKA and stgBTKA. In fact, we found that simBTKA patients received larger opioid amounts in the immediate postoperative period as well as slightly larger amounts at 30 days.