PTHrP intracrine actions divergently influence breast cancer growth through p27 and LIFR.

The role of parathyroid hormone (PTH)-related protein (PTHrP) in breast cancer remains controversial, with reports of PTHrP inhibiting or promoting primary tumor growth in preclinical studies. Here, we provide insight into these conflicting findings by assessing the role of specific biological domains of PTHrP in tumor progression through stable expression of PTHrP (-36-139aa) or truncated forms with deletion of the nuclear localization sequence (NLS) alone or in combination with the C-terminus. Although the full-length PTHrP molecule (-36-139aa) did not alter tumorigenesis, PTHrP lacking the NLS alone accelerated primary tumor growth by downregulating p27, while PTHrP lacking the NLS and C-terminus repressed tumor growth through p27 induction driven by the tumor suppressor leukemia inhibitory factor receptor (LIFR). Induction of p27 by PTHrP lacking the NLS and C-terminus persisted in bone disseminated cells, but did not prevent metastatic outgrowth, in contrast to the primary tumor site. These data suggest that the PTHrP NLS functions as a tumor suppressor, while the PTHrP C-terminus may act as an oncogenic switch to promote tumor progression through differential regulation of p27 signaling.

Development and multicentre validation of the FLEX score: personalised preoperative surgical risk prediction using attention-based ICD-10 and Current Procedural Terminology set embeddings.

BACKGROUND: Preoperative knowledge of surgical risks can improve perioperative care and patient outcomes. However, assessments requiring clinician examination of patients or manual chart review can be too burdensome for routine use. METHODS: We conducted a multicentre retrospective study of 243 479 adult noncardiac surgical patients at four hospitals within the Mass General Brigham (MGB) system in the USA. We developed a machine learning method using routinely collected coding and patient characteristics data from the electronic health record which predicts 30-day mortality, 30-day readmission, discharge to long-term care, and hospital length of stay. RESULTS: Our method, the Flexible Surgical Set Embedding (FLEX) score, achieved state-of-the-art performance to identify comorbidities that significantly contribute to the risk of each adverse outcome. The contributions of comorbidities are weighted based on patient-specific context, yielding personalised risk predictions. Understanding the significant drivers of risk of adverse outcomes for each patient can inform clinicians of potential targets for intervention. CONCLUSIONS: FLEX utilises information from a wider range of medical diagnostic and procedural codes than previously possible and can adapt to different coding practices to accurately predict adverse postoperative outcomes.

Age-Dependent Electroencephalogram Features in Infants Under Spinal Anesthesia Appear to Mirror Physiologic Sleep in the Developing Brain: A Prospective Observational Study.

BACKGROUND: Infants under spinal anesthesia appear to be sedated despite the absence of systemic sedative medications. In this prospective observational study, we investigated the electroencephalogram (EEG) of infants under spinal anesthesia and hypothesized that we would observe EEG features similar to those seen during sleep. METHODS: We computed the EEG power spectra and spectrograms of 34 infants undergoing infraumbilical surgeries under spinal anesthesia (median age 11.5 weeks postmenstrual age, range 38-65 weeks postmenstrual age). Spectrograms were visually scored for episodes of EEG discontinuity or spindle activity. We characterized the relationship between EEG discontinuity or spindles and gestational age, postmenstrual age, or chronological age using logistic regression analyses. RESULTS: The predominant EEG patterns observed in infants under spinal anesthesia were slow oscillations, spindles, and EEG discontinuities. The presence of spindles, observed starting at about 49 weeks postmenstrual age, was best described by postmenstrual age ( P =.002) and was more likely with increasing postmenstrual age. The presence of EEG discontinuities, best described by gestational age ( P = .015), was more likely with decreasing gestational age. These age-related changes in the presence of spindles and EEG discontinuities in infants under spinal anesthesia generally corresponded to developmental changes in the sleep EEG. CONCLUSIONS: This work illustrates 2 separate key age-dependent transitions in EEG dynamics during infant spinal anesthesia that may reflect the maturation of underlying brain circuits: (1) diminishing discontinuities with increasing gestational age and (2) the appearance of spindles with increasing postmenstrual age. The similarity of these age-dependent transitions under spinal anesthesia with transitions in the developing brain during physiological sleep supports a sleep-related mechanism for the apparent sedation observed during infant spinal anesthesia.

Does race or ethnicity play a role in the origin, pathophysiology, and outcomes of preeclampsia? An expert review of the literature.

The burden of preeclampsia, a substantial contributor to perinatal morbidity and mortality, is not born equally across the population. Although the prevalence of preeclampsia has been reported to be 3% to 5%, racial and ethnic minority groups such as non-Hispanic Black women and American Indian or Alaskan Native women are widely reported to be disproportionately affected by preeclampsia. However, studies that add clarity to the causes of the racial and ethnic differences in preeclampsia are limited. Race is a social construct, is often self-assigned, is variable across settings, and fails to account for subgroups. Studies of the genetic structure of human populations continue to find more variations within racial groups than among them. Efforts to examine the role of race and ethnicity in biomedical research should consider these limitations and not use it as a biological construct. Furthermore, the use of race in decision making in clinical settings may worsen the disparity in health outcomes. Most of the existing data on disparities examine the differences between White and non-Hispanic Black women. Fewer studies have enough sample size to evaluate the outcomes in the Asian, American Indian or Alaskan Native, or mixed-race women. Racial differences are noted in the occurrence, presentation, and short-term and long-term outcomes of preeclampsia. Well-established clinical risk factors for preeclampsia such as obesity, diabetes, and chronic hypertension disproportionately affect non-Hispanic Black, American Indian or Alaskan Native, and Hispanic populations. However, with comparable clinical risk factors for preeclampsia among women of different race or ethnic groups, addressing modifiable risk factors has not been found to have the same protective effect for all women. Abnormalities of placental formation and development, immunologic factors, vascular changes, and inflammation have all been identified as contributing to the pathophysiology of preeclampsia. Few studies have examined race and the pathophysiology of preeclampsia. Despite attempts, a genetic basis for the disease has not been identified. A number of genetic variants, including apolipoprotein L1, have been identified as possible risk modifiers. Few studies have examined race and prevention of preeclampsia. Although low-dose aspirin for the prevention of preeclampsia is recommended by the US Preventive Service Task Force, a population-based study found racial and ethnic differences in preeclampsia recurrence after the implementation of low-dose aspirin supplementation. After implementation, recurrent preeclampsia reduced among Hispanic women (76.4% vs 49.6%; P<.001), but there was no difference in the recurrent preeclampsia in non-Hispanic Black women (13.7 vs 18.1; P=.252). Future research incorporating the National Institute on Minority Health and Health Disparities multilevel framework, specifically examining the role of racism on the burden of the disease, may help in the quest for effective strategies to reduce the disproportionate burden of preeclampsia on a minority population. In this model, a multilevel framework provides a more comprehensive approach and takes into account the influence of behavioral factors, environmental factors, and healthcare systems, not just on the individual.

How Can We Get to Equitable and Effective Postpartum Pain Control?

Postpartum pain is common, yet patient experiences and clinical management varies greatly. In the United States, pain-related expectations and principles of adequate pain management have been framed within established norms of Western clinical medicine and a biomedical understanding of disease processes. Unfortunately, this positioning of postpartum pain and the corresponding coping strategies and pain treatments is situated within cultural biases and systemic racism. This paper summarizes the history and existing literature that examines racial inequities in pain management to propose guiding themes and suggestions for innovation. This work is critical for advancing ethical practice and establishing more effective care for all patients.

A Machine Vision-Based Method for Monitoring Broiler Chicken Floor Distribution.

The proper spatial distribution of chickens is an indication of a healthy flock. Routine inspections of broiler chicken floor distribution are done manually in commercial grow-out houses every day, which is labor intensive and time consuming. This task requires an efficient and automatic system that can monitor the chicken's floor distributions. In the current study, a machine vision-based method was developed and tested in an experimental broiler house. For the new method to recognize bird distribution in the images, the pen floor was virtually defined/divided into drinking, feeding, and rest/exercise zones. As broiler chickens grew, the images collected each day were analyzed separately to avoid biases caused by changes of body weight/size over time. About 7000 chicken areas/profiles were extracted from images collected from 18 to 35 days of age to build a BP neural network model for floor distribution analysis, and another 200 images were used to validate the model. The results showed that the identification accuracies of bird distribution in the drinking and feeding zones were 0.9419 and 0.9544, respectively. The correlation coefficient (R), mean square error (MSE), and mean absolute error (MAE) of the BP model were 0.996, 0.038, and 0.178, respectively, in our analysis of broiler distribution. Missed detections were mainly caused by interference with the equipment (e.g., the feeder hanging chain and water line); studies are ongoing to address these issues. This study provides the basis for devising a real-time evaluation tool to detect broiler chicken floor distribution and behavior in commercial facilities.

XRCC1-mediated DNA repair is associated with progression-free survival of multiple myeloma patients after autologous stem cell transplant.

Autologous stem cell transplant (ASCT) with high-dose melphalan (HDM) is the standard treatment for fit multiple myeloma (MM) patients. It is generally believed that some DNA repair proteins impact the activity to repair melphalan-induced DNA damage, thus potentially contributing to the patient's clinical response. However, knowledge of these proteins is limited. In the current study, we investigated the roles of XRCC1, a protein involved in base excision repair and single-strand break repair, in melphalan response in MM cells. Small interfering RNA knockdown of XRCC1 significantly increased the accumulation of melphalan-induced DNA damage in MM cells and sensitized them to melphalan treatment, indicating that genetic variation in XRCC1 may impact response to melphalan treatment. We then evaluated the association between an XRCC1 variant with reduced activity, rs25487 (R399Q), and clinical outcomes of 108 MM patients with melphalan therapy. Our results showed that XRCC1 rs25487 was associated with prolonged progression-free survival (PFS) in MM patients. The adjusted hazard ratio for PFS between patients carrying rs25487 AA/AG and GG was 0.42 (95% confidence interval: 0.25, 0.84, P = .014). Taken together, these results indicate that XRCC1 is involved in the repair of melphalan-induced DNA damage and XRCC1 rs25487 variant with impaired DNA repair function influences the clinical responses of HDM in MM patients.

A Raman-Based Imaging Method for Characterizing the Molecular Adsorption and Spatial Distribution of Silver Nanoparticles on Hydrated Mineral Surfaces.

Although minerals are known to affect the environmental fate and transformation of heavy-metal ions, little is known about their interaction with the heavily exploited silver nanoparticles (AgNPs). Proposed here is a combination of hitherto under-utilized micro-Raman-based mapping and chemometric methods for imaging the distribution of AgNPs on various mineral surfaces and their molecular interaction mechanisms. The feasibility of the Raman-based imaging method was tested on two macro- and microsized mineral models, muscovite [KAl2(AlSi3O10)(OH)2] and corundum (α-Al2O3), under key environmental conditions (ionic strength and pH). Both AgNPs- and AgNPs+ were found to covalently attach to corundum (pHpzc = 9.1) through the formation of Ag-O-Al- bonds and thereby to potentially experience reduced environmental mobility. Because label-free Raman imaging showed no molecular interactions between AgNPs- and muscovite (pHpzc = 7.5), a label-enhanced Raman imaging approach was developed for mapping the scarce spatial distribution of AgNPs- on such mineral surfaces. Raman maps comprising of n = 625-961 spectra for each sample/control were rapidly analyzed in Vespucci, a free open-source software, and the results were confirmed via ICP-OES, AFM, and SEM-EDX. The proposed Raman-based imaging requires minimum to no sample preparation; is sensitive, noninvasive, cost-effective; and might be extended to other environmentally relevant systems.

Probuphine (Buprenorphine) Subdermal Implants for the Treatment Of Opioid-Dependent Patients.

Probuphine (buprenorphine) subdermal implants for the treatment of opioid-dependent patients.

Management of Pregnancy and Survival of Infants with Trisomy 13 or Trisomy 18.

Objective The objective of this study was to describe antenatal/intrapartum management and survival of liveborn infants with known trisomy 13 (T13) or trisomy 18 (T18) based on planned neonatal care. Study Design This is a retrospective cohort study of singleton pregnancies complicated by T13/T18 at a tertiary center from 2004 to 2015. We included pregnancies with antenatal or neonatal cytogenetic T13/T18 diagnosis and excluded those which were terminated or had a fetal demise < 20 weeks. We compared antenatal/intrapartum management and neonatal survival by planned neonatal care, defined as either neonatal intervention (INT), including neonatal cardiopulmonary resuscitative measures or comfort care (CC) without resuscitative measures. Results In this study, 32 women (10 with T13 and 22 with T18) met study criteria; 12 (38%) elected INT and 20 (62%) CC. Compared with those who elected INT, women who elected CC were more likely to undergo elective induction (40 vs. 0%, p = 0.01), have an intrapartum stillbirth (0 vs. 32%, p = 0.14), and deliver vaginally (25 vs. 63%, p < 0.01). In neonatal survival analysis (n = 26), median survival was longer in the INT group compared with CC group (64 days [interquartile range, IQR: 2, 155) vs. 3 days [IQR]: 0.3, 42), p = 0.28), but survival to hospital discharge was similar (53 vs. 57%, p = 0.95). Conclusion Regardless of desired level of neonatal INT, many women who continue pregnancies complicated by T13/18 have infants who survive beyond hospital discharge.

Black Pregnancy-Related Mortality in the United States.

The maternal mortality rate for non-Hispanic Black birthing people is 69.9 deaths per 100,000 live births compared with 26.6 deaths per 100,000 live births for non-Hispanic White birthing people. Black pregnancy-related mortality has been underrepresented in research and the media; however, there is growing literature on the role of racism in health disparities. Those who provide care to Black patients should increase their understanding of racism's impact and take steps to center the experiences and needs of Black birthing people.

Community-level social determinants of health and pregestational and gestational diabetes.

BACKGROUND: Individual adverse social determinants of health are associated with increased risk of diabetes in pregnancy, but the relative influence of neighborhood or community-level social determinants of health is unknown. OBJECTIVE: This study aimed to determine whether living in neighborhoods with greater socioeconomic disadvantage, food deserts, or less walkability was associated with having pregestational diabetes and developing gestational diabetes. STUDY DESIGN: We conducted a secondary analysis of the prospective Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-To-Be. Home addresses in the first trimester were geocoded at the census tract level. The exposures (modeled separately) were the following 3 neighborhood-level measures of adverse social determinants of health: (1) socioeconomic disadvantage, defined by the Area Deprivation Index and measured in tertiles from the lowest tertile (ie, least disadvantage [T1]) to the highest (ie, most disadvantage [T3]); (2) food desert, defined by the United States Department of Agriculture Food Access Research Atlas (yes/no by low income and low access criteria); and (3) less walkability, defined by the Environmental Protection Agency National Walkability Index (most walkable score [15.26-20.0] vs less walkable score [<15.26]). Multinomial logistic regression was used to model the odds of gestational diabetes or pregestational diabetes relative to no diabetes as the reference, adjusted for age at delivery, chronic hypertension, Medicaid insurance status, and low household income (<130% of the US poverty level). RESULTS: Among the 9155 assessed individuals, the mean Area Deprivation Index score was 39.0 (interquartile range, 19.0-71.0), 37.0% lived in a food desert, and 41.0% lived in a less walkable neighborhood. The frequency of pregestational and gestational diabetes diagnosis was 1.5% and 4.2%, respectively. Individuals living in a community in the highest tertile of socioeconomic disadvantage had increased odds of entering pregnancy with pregestational diabetes compared with those in the lowest tertile (T3 vs T1: 2.6% vs 0.8%; adjusted odds ratio, 2.52; 95% confidence interval, 1.41-4.48). Individuals living in a food desert (4.8% vs 4.0%; adjusted odds ratio, 1.37; 95% confidence interval, 1.06-1.77) and in a less walkable neighborhood (4.4% vs 3.8%; adjusted odds ratio, 1.33; 95% confidence interval, 1.04-1.71) had increased odds of gestational diabetes. There was no significant association between living in a food desert or a less walkable neighborhood and pregestational diabetes, or between socioeconomic disadvantage and gestational diabetes. CONCLUSION: Nulliparous individuals living in a neighborhood with higher socioeconomic disadvantage were at increased odds of entering pregnancy with pregestational diabetes, and those living in a food desert or a less walkable neighborhood were at increased odds of developing gestational diabetes, after controlling for known covariates.

A framework for integrating wastewater-based epidemiology and public health.

Wastewater-based epidemiology (WBE) is an environmental approach to monitor community health through the analysis of sewage. The COVID-19 pandemic catalyzed scientists and public health professionals to revisit WBE as a tool to optimize resource allocation to mitigate disease spread and prevent outbreaks. Some studies have highlighted the value of WBE programs that coordinate with public health professionals; however, the details necessary for implementation are not well-characterized. To respond to this knowledge gap, this article documents the framework of a successful WBE program in Arizona, titled Wastewater Analysis for Tactical Epidemiological Response Systems (WATERS), detailing the developed structure and methods of communication that enabled public health preparedness and response actions. This communication illustrates how program operations were employed to reduce outbreak severity. The structure outlined here is customizable and may guide other programs in the implementation of WBE as a public health tool.

Pan-Enterovirus Characterization Reveals Cryptic Circulation of Clinically Relevant Subtypes in Arizona Wastewater.

Background: Most seasonally circulating enteroviruses result in asymptomatic or mildly symptomatic infections. In rare cases, however, infection with some subtypes can result in paralysis or death. Of the 300 subtypes known, only poliovirus is reportable, limiting our understanding of the distribution of other enteroviruses that can cause clinical disease. Objective: The overarching objectives of this study were to: 1) describe the distribution of enteroviruses in Arizona during the late summer and fall of 2022, the time of year when they are thought to be most abundant, and 2) demonstrate the utility of viral pan-assay approaches for semi-agnostic discovery that can be followed up by more targeted assays and phylogenomics. Methods: This study utilizes pooled nasal samples collected from school-aged children and long-term care facility residents, and wastewater from multiple locations in Arizona during July-October of 2022. We used PCR to amplify and sequence a region common to all enteroviruses, followed by species-level bioinformatic characterization using the QIIME 2 platform. For Enterovirus-D68 (EV-D68), detection was carried out using RT-qPCR, followed by confirmation using near-complete whole EV-D68 genome sequencing using a newly designed tiled amplicon approach. Results: In the late summer and early fall of 2022, multiple enterovirus species were identified in Arizona wastewater, with Coxsackievirus A6, EV-D68, and Coxsackievirus A19 composing 86% of the characterized reads sequenced. While EV-D68 was not identified in pooled human nasal samples, and the only reported acute flaccid myelitis case in Arizona did not test positive for the virus, an in-depth analysis of EV-D68 in wastewater revealed that the virus was circulating from August through mid-October. A phylogenetic analysis on this relatively limited dataset revealed just a few importations into the state, with a single clade indicating local circulation. Significance: This study further supports the utility of wastewater-based epidemiology to identify potential public health threats. Our further investigations into EV-D68 shows how these data might help inform healthcare diagnoses for children presenting with concerning neurological symptoms.

Maternal Cardiovascular Disease After Pre-Eclampsia and Gestational Hypertension: A Narrative Review.

Previous literature has highlighted that women who have a pregnancy affected by gestational hypertension or preeclampsia are at higher risk of cardiovascular disease (CVD) in later life. However, CVD is a composite of multiple outcomes, including coronary heart disease, heart failure, and stroke, and the risk of both CVD and hypertensive disorders of pregnancy varies by the population studied. We conducted a narrative review of the risk of cardiovascular outcomes for women with prior gestational hypertension and pre-eclampsia. Previous literature is summarized by country and ethnicity, with a higher risk of CVD and coronary heart disease observed after gestational hypertension and a higher risk of CVD, coronary heart disease and heart failure observed after pre-eclampsia in most of the populations studied. Only one study was identified in a low- or middle-income country, and the majority of studies were conducted in white or mixed ethnicity populations. We discuss potential interventions to mitigate cardiovascular risk for these women in different settings and highlight the need for a greater understanding of the epidemiology of CVD risk after gestational hypertension and pre-eclampsia outside of high-income, white populations.

Standardized Order Sets Do Not Eliminate Racial or Ethnic Inequities in Postpartum Pain Management.

Objective: To quantify the extent to which a standardized pain management order set reduced racial and ethnic inequities in post-cesarean pain evaluation and management. Methods: We conducted a retrospective cohort study to quantify racial and ethnic differences in pain evaluation and management before (July 2014-June 2016) and after implementation of a standardized post-cesarean order set (March 2017-February 2018). Electronic medical records were queried for pain scores >7/10, number of pain assessments, and opioid, nonsteroidal anti-inflammatory drug (NSAID), and acetaminophen doses. Outcomes were grouped into 0 to <24 and 24-48 h postpartum, and stratified by race/ethnicity (Hispanic, non-Hispanic Black [NHB], non-Hispanic White [NHW], Asian, and other), as documented in the electronic health record. Analyses included logistic regression for the categorical outcome of pain score >7 (severe pain), and linear regression, with propensity score adjustment. Main effect and interaction terms were used to calculate the difference-in-difference in pain process and outcome measures between the baseline and follow-up periods. Results: After order set implementation (N=888), severe pain remained more common among NHB patients (% pain scores >7 NHW vs. NHB 0 to <24 h: 22% vs. 33%, p=0.003; 24-48 h: 26% vs. 40%, p<0.001). Among all patients, pain management processes changed after implementation of the order set, with overall fewer assessments, less Opioids, and more nonopioid analgesics. However, racial and ethnic inequities in a number of assessments and in treatment were unchanged (all p for interaction >0.05), with the exception of a modest increase in NSAID doses 24-48 h postpartum for Hispanic patients. Conclusion: A standardized pain management order set reduced overall postpartum opioid use, but did not reduce racial and ethnic disparities in pain evaluation and management. Future work should investigate racial equity-focused education and interventions designed to eliminate disparities in pain management.

Postpartum medication for opioid use disorder outcomes associated with prenatal treatment and neighborhood-level social determinants.

BACKGROUND: Opioid use disorder is a leading cause of death through the year postpartum. OBJECTIVE: This study aimed to identify the association of neighborhood-level social determinants of health and prenatal opioid use disorder treatment receipt with the outcomes of medication treatment for opioid use disorder through the year postpartum among a cohort of birthing people. STUDY DESIGN: This was a population-based retrospective cohort study that used state Medicaid claims and enrollment data for the 1690 individuals who delivered a live infant between July 1, 2016 and December 31, 2020 and received medication for opioid use disorder at delivery. The primary exposure was the state Health Opportunity Index, a composite measure of social determinants of health linked at the census-tract level. Secondary exposures included comprehensiveness of opioid use disorder treatment and duration of medication treatment for opioid use disorder received prenatally. Outcomes included the duration and continuity of postpartum medication treatment for opioid use disorder, operationalized as the time from delivery to the discontinuation of medication treatment for opioid use disorder, and percentage of days covered by medication treatment for opioid use disorder within the 12 months after delivery, respectively. RESULTS: Within the study sample, 711 deliveries were to birthing people in the lowest state Health Opportunity Index tercile (indicating high burden of negative social determinants of health), 647 in the middle state Health Opportunity Index tercile, and 332 in the highest state Health Opportunity Index tercile. Using stepwise multivariable regression (Cox proportional hazards and negative binomial models) guided by a socioecological framework, prenatal receipt of more comprehensive opioid use disorder treatment and/or longer duration of prenatal medication treatment for opioid use disorder was associated with improved 1-year postpartum opioid use disorder treatment outcomes (duration and continuity of medication treatment for opioid use disorder). When the state Health Opportunity Index was added to the models, these significant associations remained stable, with the state Health Opportunity Index not demonstrating an association with the outcomes (duration hazard ratio, 1.39; 95% confidence interval, 0.551-3.512; continuity relative risk, 1.024; 95% confidence interval, 0.323-3.247). CONCLUSION: Targeted efforts at expanding access to and quality of evidence-based opioid use disorder treatments for reproductive-age people across the life course should be prioritized within the spectrum of work aimed at eradicating disparities in pregnancy-related mortality.