Validation of an Electronic Health Record-Based Machine Learning Model Compared to Clinical Risk Scores for Gastrointestinal Bleeding.

BACKGROUND & AIMS: Guidelines recommend use of risk stratification scores for patients presenting with gastrointestinal bleeding (GIB) to identify very-low-risk patients eligible for discharge from emergency departments. Machine learning models may outperform existing scores and can be integrated within the electronic health record (EHR) to provide real-time risk assessment without manual data entry. We present the first EHR-based machine learning model for GIB. METHODS: The training cohort comprised 2,546 patients and internal validation of 850 patients presenting with overt GIB (hematemesis, melena, hematochezia) to emergency departments of 2 hospitals from 2014-2019. External validation was performed on 926 patients presenting to a different hospital with the same EHR from 2014-2019. The primary outcome was a composite of red-blood-cell transfusion, hemostatic intervention (endoscopic, interventional radiologic, or surgical), and 30-day all-cause mortality. We used structured data fields in the EHR available within 4 hours of presentation and compared performance of machine learning models to current guideline-recommended risk scores, Glasgow-Blatchford Score (GBS) and Oakland Score. Primary analysis was area under the receiver-operating-characteristic curve (AUC). Secondary analysis was specificity at 99% sensitivity to assess proportion of patients correctly identified as very-low-risk. RESULTS: The machine learning model outperformed the GBS (AUC=0.92 vs. 0.89;p<0.001) and Oakland score (AUC=0.92 vs. 0.89;p<0.001). At the very-low-risk threshold of 99% sensitivity, the machine learning model identified more very-low-risk patients: 37.9% vs. 18.5% for GBS and 11.7% for Oakland score (p<0.001 for both comparisons). CONCLUSIONS: An EHR-based machine learning model performs better than currently recommended clinical risk scores and identifies more very-low-risk patients eligible for discharge from the emergency department.

A Hemoglobinopathy That Produces an Array of Different Hemoglobin A1c Values.

Hemoglobin A1c (HbA1c) refers to non-enzymatically glycated hemoglobin and reflects the patient's glycemic status over approximately 3 months. An elevated HbA1c over 6.5% National Glycohemoglobin Standardization Program (NGSP) (48 mmol/mol the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC)) can be used to diagnose diabetes mellitus. In our laboratory, HbA1c is determined by ion-exchange chromatography which has the advantage of detecting common Hb variants such as Hb S, C, E and D without adversely affecting the HbA1c determination. Certain homozygous or compound heterozygous hemoglobinopathies such as homozygous sickle disease and Hb SC disease can significantly lower the HbA1c by reducing red cell lifespan. Occasionally however, rare and mostly benign hemoglobinopathies can interfere with this technique resulting in an apparent elevation of HbA1c in an otherwise non-diabetic patient. In this report, we describe such a hemoglobinopathy termed Hb Wayne that resulted in a significant HbA1c elevation in a normoglycemic individual. HbA1c was determined by multiple methods including immunoassay, a modified capillary electrophoresis and an alternative ion-exchange system. These techniques yielded significantly lower A1c results, more in keeping with the patient's clinical background. The alternative ion-exchange system resulted in a low A1c that was qualified by warning flags on the chromatogram that indicated the result was not reportable. The hemoglobinopathy in question, Hb Wayne, is a frameshift mutation in the alpha globin gene that results in an extended alpha globin polypeptide that can form two variants Hb Wayne I and Wayne II. Hb Wayne is a clinically silent asymptomatic disorder with no hematologic consequences. The artifactual elevation of HbA1c is, in contrast, very significant because it may result in a misdiagnosis of diabetes mellitus leading to unnecessary treatment. In this report, we compare our findings with other descriptions of Hb Wayne in the literature and corroborate a number of previous observations and conclusions.

Assessment of Antimicrobial Therapy in Eradicating Chlamydia muridarum in Research Mice: Immune Status and its Impact on Outcomes.

Chlamydia muridarum (Cm) is a moderately prevalent, gram-negative, intracellular bacterium that affects laboratory mice, causing subclinical to severe disease, depending on the host's immune status. The effectiveness of various antibiotic regimens aimed at eradicating Cm in both immunodeficient and immunocompetent laboratory mice was evaluated. NSG mice were cohoused with Cm-shedding BALB/cJ mice for 14 days to simulate natural exposure. Four groups of 8 infected NSG mice were treated for 7 days with either 0.08% sulfamethoxazole and 0.016% trimethoprim (TMS) in water, 0.0625% doxycycline in feed, 0.124%/0.025% TMS in feed, or 0.12% amoxicillin in feed. A control group was provided standard water and feed. The impact of treatment on gastrointestinal microbiota (GM) was performed through shotgun sequencing on the last day of treatment. TMS and Amoxicillin had negligible effects on GM, while doxycycline had the largest effect. All antibiotic treated NSG mice exhibited clinical disease, including dehydration, hunched posture, >20% weight loss, and dyspnea, leading to euthanasia 21-40 days post-treatment (32.6 ± 4.2 days; mean ± SD). Untreated controls were euthanized 14-33 days post-exposure (23.75 ± 5.9 days). All mice were fecal PCR positive for Cm at euthanasia. Histological evaluation revealed multifocal histiocytic and neutrophilic bronchointerstitial pneumonia and/or bronchiolitis featuring prominent intralesional chlamydial inclusion bodies in all mice. Subsequently, groups of 8 C57BL/6J, BALB/cJ, NOD.SCID, and NSG mice infected with Cm were treated with 0.124%/0.025% TMS in feed for 7 (BALB/cJ and C57BL/6J) or 21 days (NSG and NOD.SCID). All immunocompetent and NOD.SCID mice were negative for Cm by PCR 14 days post-treatment, remained clinically normal and had no evidence of Cm infection at necropsy, all NSG mice remained Cm positive and were euthanized. While these findings highlight the difficulties in eradicating Cm from highly immunodeficient mice, eradication of Cm from immunocompetent or moderately immunocompromised mice with antibiotics is feasible.

Plasmapheresis in ANCA-Associated Vasculitis with Active Kidney Involvement in the United States (2016-2020): A Cross-Sectional Study.

INTRODUCTION: Plasmapheresis is currently recommended when antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) presents with severe kidney and/or lung involvement. This cross-sectional study aimed at describing characteristics of hospitalized patients diagnosed with AAV with severe kidney involvement undergoing plasmapheresis in the US. METHODS: We defined the study population as adults hospitalized for active kidney involvement with a new diagnosis of AAV (by subtype or unspecified). We established the cohort from the 2016-2020 National Inpatient Sample by ICD-10-CM codes. In this cross-sectional study, we described demographic and clinical characteristics, associated inpatient procedures, lengths of stay, hospital costs, and disposition at discharge comparing patients treated and not treated with plasmapheresis. RESULTS: We identified a total of 975 cases of hospitalized AAV with acute kidney involvement in the US treated by plasmapheresis over the 5-year period. Demographic characteristics of patients who received plasmapheresis were similar to those in patients who did not (n=5670). There were no regional differences in the proportion of patients who received plasmapheresis; however, plasmapheresis was deployed more frequently among patients admitted to urban teaching hospitals relative to rural and non-teaching hospitals. Cases treated with plasmapheresis were more likely to have had acute kidney injury (AKI) (96% vs. 90%, p=0.0007), AKI requiring dialysis (52% vs 16%, p<0.001), hypoxia (40% vs. 16%, p<0.0001), and respiratory failure requiring mechanical ventilation (13% vs. 3%, p=0.0003). CONCLUSION: During 2016-2020, plasmapheresis was deployed in approximately 20% of patients being admitted for AAV and acute kidney involvement in the US. As standards of care and practice evolve, the role of plasmapheresis in the management of AAV with acute kidney involvement will require further study.

Crystalline Antimony Selenide Thin Films for Optoelectronics through Photonic Curing.

Thermal annealing is the most common postdeposition technique used to crystallize antimony selenide (Sb2Se3) thin films. However, due to slow processing speeds and a high energy cost, it is incompatible with the upscaling and commercialization of Sb2Se3 for future photovoltaics. Herein, for the first time, a fast-annealing technique that uses millisecond light pulses to deliver energy to the sample is adapted to cure thermally evaporated Sb2Se3 films. This study demonstrates how photonic curing (PC) conditions affect the outcome of Sb2Se3 phase conversion from amorphous to crystalline by evaluating the films' crystalline, morphological, and optical properties. We show that Sb2Se3 is readily converted under a variety of different conditions, but the zone where suitable films for optoelectronic applications are obtained is a small region of the parameter space. Sb2Se3 annealing with short pulses (<3 ms) shows significant damage to the sample, while using longer pulses (>5 ms) and a 4-5 J cm-2 radiant energy produces (211)- and (221)-oriented crystalline Sb2Se3 with minimal to no damage to the sample. A proof-of-concept photonically cured Sb2Se3 photovoltaic device is demonstrated. PC is a promising annealing method for large-area, high-throughput annealing of Sb2Se3 with various potential applications in Sb2Se3 photovoltaics.

Quantification of neurofilament light and glial fibrillary acidic protein in finger-prick blood.

An accurate diagnosis of neurodegenerative disease and traumatic brain injury is important for prognostication and treatment. Neurofilament light and glial fibrillary acidic protein (GFAP) are leading biomarkers for neurodegeneration and glial activation that are detectable in blood. Yet, current recommendations require rapid centrifugation and ultra-low temperature storage post-venepuncture. Here, we investigated if these markers can be accurately measured in finger-prick blood using dried plasma spot cards. Fifty patients (46 with dementia; 4 with traumatic brain injury) and 19 healthy volunteers underwent finger-prick and venous sampling using dried plasma spot cards and aligned plasma sampling. Neurofilament light and GFAP were quantified using a Single molecule array assay and correlations between plasma and dried plasma spot cards assessed. Biomarker concentrations in plasma and finger-prick dried plasma spot samples were significantly positively correlated (neurofilament light ρ = 0.57; GFAP ρ = 0.58, P < 0.001). Finger-prick neurofilament light and GFAP were significantly elevated after acute traumatic brain injury with non-significant group-level increases in dementia (91% having Alzheimer's disease dementia). In conclusion, we present preliminary evidence that quantifying GFAP and neurofilament light using finger-prick blood collection is viable, with samples stored at room temperature using dried plasma spot cards. This has potential to expand and promote equitable testing access, including in settings where trained personnel are unavailable to perform venepuncture.

One-Stop-Shop Cancer Screening Clinic: Acceptability Testing.

Cancer screenings aid in the early detection of cancer and can help reduce cancer-related mortality. The current model of care for cancer screening is often siloed, based on the targeted cancer site. We tested the acceptability of a new model of care, called the One-Stop-Shop Cancer Screening Clinic, that centralizes cancer screenings and offers patients the option to complete all their recommended cancer screenings within one to two visits. We administered surveys to 59 community members and 26 healthcare providers to gather feedback about the One-Stop-Shop model of care. Both community members and providers identified potential benefits (e.g., decreased patient burden, increased completion of cancer screenings) and also potential challenges (e.g., challenges with workflow and timing of care) of the model of care. The results of the study support the acceptability of the model of care. Of the community members surveyed, 89.5% said, if offered, they would be interested in participating in the One-Stop-Shop Cancer Screening Clinic. Future studies are needed to formally evaluate the impact and cost effectiveness of the One-Stop-Shop Cancer Screening Clinic.

MEK1/2 and ERK1/2 mediated lung endothelial injury and altered hemostasis promote diffuse alveolar hemorrhage in murine lupus.

OBJECTIVE: About 3% of lupus patients develop severe diffuse alveolar hemorrhage (DAH) with pulmonary vasculitis. B6 mice with pristane-induced lupus also develop DAH, but BALB/c mice are resistant. DAH is independent of TLR signaling and other inflammatory pathways. This study examined the role of the mitogen-activated protein kinase pathway (MEK1/2-ERK1/2, JNK, p38). METHODS: B6 and BALB/c mice were treated with pristane ± inhibitors of MEK1/2 (trametinib/GSK1120212, "GSK"), ERK1/2 (SCH772984, "SCH"), JNK, or p38. Effects on lung hemorrhage and hemostasis were determined. RESULTS: GSK and SCH abolished DAH, whereas JNK and p38 inhibitors were ineffective. Apoptotic cells were present in lung from pristane-treated mice, but not mice receiving pristane+GSK and endothelial dysfunction was normalized. Expression of the ERK1/2-regulated transcription factor Egr1 increased in pristane-treated B6, but not BALB/c, mice and was normalized by GSK. Pristane also increased expression of the anticoagulant genes Tfpi (tissue factor pathway inhibitor) and Thbd (thrombomodulin) in B6 mice. The ratio of tissue factor (F3) to Tfpi increased in B6 (but not BALB/c) mice and was normalized by GSK. Circulating Thbd protein increased in B6 mice and returned to normal after GSK treatment. Consistent with augmented endothelial anticoagulant activity, pristane treatment increased tail bleeding in B6 mice. CONCLUSION: Pristane treatment promotes lung endothelial injury and DAH in B6 mice by activating the MEK1/2-ERK1/2 pathway and impairing hemostasis. The hereditary factors determining susceptibility to lung injury and bleeding in pristane-induced lupus are relevant to the pathophysiology of life-threatening DAH in SLE and may help to optimize therapy.

'I need to understand so we can decide together': Difficult conversations about alopecia areata.

The management of alopecia areata (AA) in pediatric patients poses unique challenges, particularly regarding treatment discussions and decision making involving both patients and their families. This commentary presents findings from unpublished research on treatment-discontinuation discussions between AA patients and their treating providers, shedding light on the hopes, expectations, and disappointments of individuals with severe AA. The study explored patient and guardian satisfaction with these discussions, emphasizing the importance of addressing psychosocial concerns, facilitating contact with support groups, and demonstrating empathy. The role of dermatologists in conversations about treatment, prognosis, and quality of life is examined, emphasizing the need for honesty, empathy, and realistic expectations. The authors propose a patient-centered approach to initiating and guiding discussions, focusing on understanding the impact of AA on patients and their families and collaboratively deciding on treatment options. The mantra: 'I need to understand how this is affecting all of you, so we can decide together what to do next' is central to this proposed approach. Special considerations for different scenarios are discussed, highlighting the importance of individualized care and effective communication. Overall, the commentary emphasizes the significance of actively listening, acknowledging emotions, and prioritizing patient and family goals to optimize care for pediatric AA patients.

A New Perspective to Interpret How the Vestibular Efferent System Correlates the Complexity of Routine Balance Maintenance with Management of Emergency Fall Prevention Strategies.

Bipedalism is unique among mammals. Until modern times, a fall and resulting leg fracture could be fatal. Balance maintenance after a destabilizing event requires instantaneous decision making. The vestibular system plays an essential role in this process, initiating an emergency response. The afferent otolithic neural response is the first directionally oriented information to reach the cortex, and it can then be used to initiate an appropriate protective response. Some vestibular efferent axons feed directly into type I vestibular hair cells. This allows for rapid vestibular feedback via the striated organelle (STO), which has been largely ignored in most texts. We propose that this structure is essential in emergency fall prevention, and also that the system of sensory detection and resultant motor response works by having efferent movement information simultaneously transmitted to the maculae with the movement commands. This results in the otolithic membrane positioning itself precisely for the planned movement, and any error is due to an unexpected external cause. Error is fed back via the vestibular afferent system. The efferent system causes macular otolithic membrane movement through the STO, which occurs simultaneously with the initiating motor command. As a result, no vestibular afferent activity occurs unless an error must be dealt with.

Hybrid Versus Conventional Colorectal Endoscopic Submucosal Dissection: A Multicenter Randomized Controlled Trial (Short-Endoscopic Submucosal Dissection).

INTRODUCTION: Hybrid endoscopic submucosal dissection (H-ESD), which utilizes ESD knife along with snare-based resection, has been developed to overcome the technical complexity of conventional ESD (C-ESD). The aim of this study was to compare the therapeutic outcomes of H-ESD vs C-ESD for nonpedunculated colorectal lesions ≥20 mm in size. METHODS: We conducted a multicenter randomized controlled trial to compare H-ESD and C-ESD (Short-ESD trial). Patients with colorectal lesions between 20 and 50 mm in size were randomly assigned (1:1) to H-ESD or C-ESD. Primary outcome was procedure time/speed. Secondary outcomes were en bloc and complete (R0) resection rates and adverse event rates. RESULTS: A total of 89 patients (median age 63 years; 49.3% women) with the median polyp size of 30 mm underwent H-ESD (n = 40) and C-ESD (n = 49). The mean procedure time of H-ESD was significantly shorter than that of C-ESD (41.1 ± 16.3 vs 54.3 ± 28.2 minutes; P = 0.007). The en bloc and R0 resection rates trended lower in the H-ESD vs C-ESD groups (77.5% vs 87.8%; P = 0.26% and 72.5% vs 79.6%; P = 0.46) without reaching statistical significance. Adverse event rate was similar between H-ESD and C-ESD (10% vs 8.2%; P = 1.00). DISCUSSION: Both H-ESD and C-ESD were safe and effective for resection of large colorectal lesions. H-ESD was associated with a shorter procedure time. H-ESD may represent a viable alternative to C-ESD, with the main advantage being easy applicability of a snare-based technique for colorectal lesions. Future studies are needed to further define the most suitable lesions for H-ESD, as to optimize efficiency and safety without compromising resection outcomes. ClinicaTrials.gov NCT NCT05347446.

Hearing outcomes following reimplantation of functional legacy cochlear implants.

OBJECTIVES: Recently, patients with certain legacy cochlear implants (CIs) have sought out reimplantation to enjoy the benefits offered by newer processor technology. This decision can be difficult, especially when the individual relies exclusively on the device for communication and scores at the ceiling of performance metrics. To date, most outcome data is derived from reimplantation of a non-functioning CI-a relatively easy decision. The aim of this study is to report hearing outcomes following reimplantation of legacy implants to guide surgeons and patients approaching this high-stakes clinical situation. PATIENTS AND INTERVENTION: Four patients implanted with Advanced Bionics Clarion C1 devices over 20 years ago underwent reimplantation. RESULTS: Three reimplanted patients demonstrated a maintenance or improvement in their audiometric performance with one patient experiencing only a 5 % decrease in AzBioQ score. Each patient expressed satisfaction with the expansion of technological capabilities including improved battery life, and device connectivity. There were no failed reimplantations or other adverse effects. CONCLUSIONS: Reimplantation of a functioning legacy CI result in stability or improvement in auditory performance. All individuals in this series report that they enjoy the new connectivity and programming technologies. As the rate advancement in CI technology continues to increase and newer device architectures emerge, these data will help to inform the decision to reimplant functioning devices.

Staged implantation of active transcutaneous bone conduction hearing devices (BCHD) after explantation of older generation bone anchored hearing aids (BAHAs): Surgical outcomes and approach to management.

PURPOSE: To evaluate outcomes following explantation of percutaneous or transcutaneous bone conduction implants (pBCIs or tBCIs) and subsequent implantation of transcutaneous active bone conduction hearing devices (BCHDs); to provide guidance regarding staging of surgery and adjunctive procedures. MATERIALS AND METHODS: Retrospective chart review of eight adult subjects (ten ears) with pBCIs or tBCIs who underwent explantation of their device and subsequent implantation with a BCHD [MED-EL BONEBRIDGE™ (n = 7, 70 %) or Cochlear™ Osia® (n = 3, 30 %)]. RESULTS: Reasons for pBCI or tBCI explantation were pain (60 %, 6/10), infection (60 %, 6/10), skin overgrowth (50 %, 5/10), and inability to obtain new processors (20 %, 2/10). Median time between pBCI or tBCI removal and BCHD staged implant was 4.7 (IQR 2.2-8.1) months. Two subjects developed complications following BCHD implantation. One had a persistent wound overlying the osseointegrated screw after removal of the pBCI abutment, requiring removal and temporalis rotational flap. Staged Osia® implantation was performed, but ultimately wound dehiscence developed over the device. The second subject experienced an infection after BONEBRIDGE™ implantation (32 days after pBCI explant), necessitating washout and treatment with intravenous antibiotics. There was subsequent device failure. CONCLUSION: The transition from a pBCI or tBCI to a novel transcutaneous device is nuanced. Staged pBCI or tBCI explantation and novel BCHD implantation with sufficient time for wound healing is vital. Adjunctive procedures to augment soft tissue in cases of prior attenuation may be required to avoid complications with larger internal devices.

Feasibility and acceptability of measuring positivity resonance in nurse-patient telehealth videoconferencing visits: A mixed-methods observational study.

AIM: To investigate the feasibility and acceptability of the training process, procedures, measures and recruitment strategies necessary for a future investigation to test the reliability and validity of using positivity resonance measures in health care encounters. BACKGROUND: Although the measurement of positivity resonance is promising, and non-participant observation is considered effective, their approaches to studying nurse-patient relationships have not been fully explored. DESIGN: A mixed-methods observational study. METHODS: Video recordings of 30 nurse-patient dyads completing telehealth video visit encounters were edited and coded using behavioural indicators of positivity resonance. A post-visit survey gathered data on the participants' perceptions of positivity resonance and the study procedures. The research team completed memos and procedural logs to provide narrative data on the study's training, coding, recruitment and operational procedures. The study included 33 persons with cancer and 13 oncology nurses engaging in telehealth video visit encounters at an academic oncology ambulatory care center located in the southeastern United States. RESULTS: Study procedures were found to be feasible and acceptable to participants. An adequate sample of participants (N = 46) were enrolled and retained in the study. Interrater reliability, as evidenced by Cohen's weighted kappa, ranged from .575 to .752 and interclass correlation coefficients >.8 were attainable within a reasonable amount of time and with adequate training. Behavioural indicators of positivity resonance were observed in all telehealth visits and reported by the participants in the perceived positivity resonance survey. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist guided reporting. CONCLUSIONS: Designing research around the concept of positivity resonance is an innovative and feasible approach to exploring how rapport is cultivated within nurse-patient relationships. RELEVANCE TO PROFESSIONAL PRACTICE: Measuring positivity resonance may hold promise for exploring patient and nurse outcomes including trust, responsiveness, health-related behaviours, well-being, resilience and satisfaction. REPORTING METHOD: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist guided the reporting of results to ensure that adequate details of the study were provided to ensure an accurate and complete report. PATIENT OR PUBLIC CONTRIBUTION: Planning of the research design and study procedures was done in consultation with nurse clinicians with experience with telehealth and managers responsible within the practice setting where the study was conducted. This ensured the study procedures were ethical, safe, secure and did not create unnecessary burden to the study participants. The study included collecting data from nurse and patient participants about the acceptability of the study procedures.

Reproducible preclinical models of androgen receptor driven human prostate cancer bone metastasis.

BACKGROUND: Preclinical models recapitulating the metastatic phenotypes are essential for developing the next-generation therapies for metastatic prostate cancer (mPC). We aimed to establish a cohort of clinically relevant mPC models, particularly androgen receptor positive (AR+) bone metastasis models, from LuCaP patient-derived xenografts (PDX) that reflect the heterogeneity and complexity of mPC. METHODS: PDX tumors were dissociated into single cells, modified to express luciferase, and were inoculated into NSG mice via intracardiac injection. The progression of metastases was monitored by bioluminescent imaging. Histological phenotypes of metastases were characterized by immunohistochemistry and immunofluorescence staining. Castration responses were further investigated in two AR-positive models. RESULTS: Our PDX-derived metastasis (PDM) model collection comprises three AR+ adenocarcinomas (ARPC) and one AR- neuroendocrine carcinoma (NEPC). All ARPC models developed bone metastases with either an osteoblastic, osteolytic, or mixed phenotype, while the NEPC model mainly developed brain metastasis. Different mechanisms of castration resistance were observed in two AR+ PDM models with distinct genotypes, such as combined loss of TP53 and RB1 in one model and expression of AR splice variant 7 (AR-V7) expression in another model. Intriguingly, the castration-resistant tumors displayed inter- and intra-tumor as well as organ-specific heterogeneity in lineage specification. CONCLUSION: Genetically diverse PDM models provide a clinically relevant system for biomarker identification and personalized medicine in metastatic castration-resistant prostate cancer.

Prophylactic Unfractionated Heparin in Antepartum Hospitalizations: A Randomized Controlled Trial.

OBJECTIVE: To assess the effect of gestational age-based dosing of unfractionated heparin (UFH) compared with standard dosing of UFH for thromboprophylaxis on an elevated serum activated partial thromboplastin time (aPTT) during prolonged antepartum hospitalizations. METHODS: This was a randomized trial of pregnant persons who were admitted in the antepartum period for at least 72 hours. Participants were randomly allocated to the standard dose of UFH (5,000 units subcutaneously every 12 hours) or the gestational age-based dose of UFH (first trimester [less than 14 weeks]: 5,000 units subcutaneously every 12 hours; second trimester [14-27 6/7 weeks]: 7,500 units subcutaneously every 12 hours; third trimester (28 weeks or more): 10,000 units subcutaneously every 12 hours). The primary outcome was the proportion of antepartum patients who had an elevated serum aPTT value above the normal range (more than 36.2 seconds) 6 hours after an UFH dose. Secondary outcomes included the development of venous thromboembolism (VTE) and reported side effects of heparin administration. RESULTS: Between December 15, 2020, and April 1, 2022, 97 patients with antepartum hospitalizations were screened and 46 were randomized: 22 allocated to standard dosing and 24 allocated to gestational age-based dosing of UFH. A significantly greater proportion of antepartum patients who received gestational age-based dosing had an abnormal elevation in aPTT compared with those who received standard dosing (33.3% vs 4.8%, P =.02). Gestational age-based dosing resulted in higher maximum [interquartile range] aPTT (30.4 [27.4, 37.5] vs 26.6 [23.0, 29.6], P =.01) and anti-Xa levels (0.09 [0.09, 0.11] vs 0.09 [0.09, 0.09], P =.04). There was no significant difference in VTE between groups ( P =.47). CONCLUSION: Gestational age-based dosing of UFH for thromboprophylaxis of antepartum hospitalizations was associated with significantly increased rates of elevated coagulation parameters compared with standard fixed dosing. This study suggests a need for close monitoring if higher doses of UFH during pregnancy are used later in gestation. The efficacy of gestational age-based dosing compared with standard dosing for UFH to prevent thromboembolic events remains an area for future investigation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT04635839.

Association between physician age and patterns of end-of-life care among older Americans.

BACKGROUND: End-of-life (EOL) care patterns may differ by physician age given differences in how physicians are trained or changes associated with aging. We sought to compare patterns of EOL care delivered to older Americans according to physician age. METHODS: We conducted a cross-sectional study of a 20% sample of Medicare fee-for-service beneficiaries aged ≥66 years who died in 2016-2019 (n = 487,293). We attributed beneficiaries to the physician who had >50% of primary care visits during the last 6 months of life. We compared beneficiary-level outcomes by physician age (<40, 40-49, 50-59, or ≥60) in two areas: (1) advance care planning (ACP) and palliative care; and (2) high-intensity care at the EOL. RESULTS: Beneficiaries attributed to younger physicians had slightly higher proportions of billed ACP (adjusted proportions, 17.1%, 16.1%, 15.5%, and 14.0% for physicians aged <40, 40-49, 50-59, and ≥60, respectively; p-for-trend adjusted for multiple comparisons <0.001) and palliative care counseling or hospice use in the last 180 days of life (64.5%, 63.6%, 61.9%, and 60.8%; p-for-trend <0.001). Similarly, physicians' younger age was associated with slightly lower proportions of emergency department visits (57.4%, 57.0%, 57.4%, and 58.1%; p-for-trend <0.001), hospital admissions (51.2%, 51.1%, 51.4%, and 52.1%; p-for-trend <0.001), intensive care unit admissions (27.8%, 27.9%, 28.2%, and 28.3%; p-for-trend = 0.03), or mechanical ventilation or cardiopulmonary resuscitation (14.2, 14.9%, 15.2%, and 15.3%; p-for-trend <0.001) in the last 30 days of life, and in-hospital death (20.2%, 20.6%, 21.3%, and 21.5%; p-for-trend <0.001). CONCLUSIONS: We found that differences in patterns of EOL care between beneficiaries cared for by younger and older physicians were small, and thus, not clinically meaningful. Future research is warranted to understand the factors that can influence patterns of EOL care provided by physicians, including initial and continuing medical education.

MEK1/2 and ERK1/2 mediated lung endothelial injury and altered hemostasis promote diffuse alveolar hemorrhage in murine lupus.

Objective: About 3% of lupus patients develop severe diffuse alveolar hemorrhage (DAH) with pulmonary vasculitis. B6 mice with pristane-induced lupus also develop DAH, but BALB/c mice are resistant. DAH is independent of TLR signaling and other inflammatory pathways. This study examined the role of the mitogen-activated protein kinase pathway (MEK1/2-ERK1/2, JNK, p38). Methods: B6 and BALB/c mice were treated with pristane ± inhibitors of MEK1/2 (trametinib/GSK1120212, "GSK"), ERK1/2 (SCH772984, "SCH"), JNK, or p38. Effects on lung hemorrhage and hemostasis were determined. Results: GSK and SCH abolished DAH, whereas JNK and p38 inhibitors were ineffective. Apoptotic cells were present in lung from pristane-treated mice, but not mice receiving pristane+GSK and endothelial dysfunction was normalized. Expression of the ERK1/2-regulated transcription factor Egr1 increased in pristane-treated B6, but not BALB/c, mice and was normalized by GSK. Pristane also increased expression of the anticoagulant genes Tfpi (tissue factor pathway inhibitor) and Thbd (thrombomodulin) in B6 mice. The ratio of tissue factor ( F3 ) to Tfpi increased in B6 (but not BALB/c) mice and was normalized by GSK. Circulating Thbd protein increased in B6 mice and returned to normal after GSK treatment. Consistent with augmented endothelial anticoagulant activity, pristane treatment increased tail bleeding in B6 mice. Conclusion: Pristane treatment promotes lung endothelial injury and DAH in B6 mice by activating the MEK1/2-ERK1/2 pathway and impairing hemostasis. The hereditary factors determining susceptibility to lung injury and bleeding in pristane-induced lupus are relevant to the pathophysiology of life-threatening DAH in SLE and may help to optimize therapy.

Controlled production of lipopolysaccharides increases immune activation in Salmonella treatments of cancer.

Immunotherapies have revolutionized cancer treatment. These treatments rely on immune cell activation in tumours, which limits the number of patients that respond. Inflammatory molecules, like lipopolysaccharides (LPS), can activate innate immune cells, which convert tumour microenvironments from cold to hot, and increase therapeutic efficacy. However, systemic delivery of lipopolysaccharides (LPS) can induce cytokine storm. In this work, we developed immune-controlling Salmonella (ICS) that only produce LPS in tumours after colonization and systemic clearance. We tuned the expression of msbB, which controls production of immunogenic LPS, by optimizing its ribosomal binding sites and protein degradation tags. This genetic system induced a controllable inflammatory response and increased dendritic cell cross-presentation in vitro. The strong off state did not induce TNFα production and prevented adverse events when injected into mice. The accumulation of ICS in tumours after intravenous injection focused immune responses specifically to tumours. Tumour-specific expression of msbB increased infiltration of immune cells, activated monocytes and neutrophils, increased tumour levels of IL-6, and activated CD8 T cells in draining lymph nodes. These immune responses reduced tumour growth and increased mouse survival. By increasing the efficacy of bacterial anti-cancer therapy, localized production of LPS could provide increased options to patients with immune-resistant cancers.