RESUMEN

PURPOSE: MDM2, a negative regulator of the TP53 tumor suppressor, is oncogenic when amplified. MDM2 amplification (MDM2amp) is mutually exclusive with TP53 mutation and is seen in 6% of patients with lung adenocarcinoma (LUAD), with significant enrichment in subsets with receptor tyrosine kinase (RTK) driver alterations. Recent studies have shown synergistic activity of MDM2 and MEK inhibition in patient-derived LUAD models with MDM2amp and RTK driver alterations. However, the combination of MDM2 and RTK inhibitors in LUAD has not been studied. METHODS: We evaluated the combination of MDM2 and RTK inhibition in patient-derived models of LUAD. RESULTS: In a RET-fusion LUAD patient-derived model with MDM2amp, MDM2 inhibition with either milademetan or AMG232 combined with selpercatinib resulted in long-term in vivo tumor control markedly superior to either agent alone. Similarly, in an EGFR-mutated model with MDM2amp, combining either milademetan or AMG232 with osimertinib resulted in long-term in vivo tumor control, which was strikingly superior to either agent alone. CONCLUSION: These preclinical in vivo data provide a rationale for further clinical development of this combinatorial targeted therapy approach.

Asunto(s)

RESUMEN

BACKGROUND: With limitations of conventional imaging and biopsy, accurate, non-invasive techniques to detect clear-cell renal cell carcinoma in patients with renal masses remain an unmet need. 89Zr-labelled monoclonal antibody ([89Zr]Zr-girentuximab) has high affinity for carbonic anhydrase 9, a tumour antigen highly expressed in clear-cell renal cell carcinoma. We aimed to evaluate [89Zr]Zr-girentuximab PET-CT imaging for detection and characterisation of clear-cell renal cell carcinoma. METHODS: ZIRCON was a prospective, open-label, multicentre, phase 3 trial conducted at 36 research hospitals and practices across nine countries (the USA, Australia, Canada, the UK, Türkiye, Belgium, the Netherlands, Spain, and France). Patients aged 18 years or older with an indeterminate renal mass 7 cm or smaller (cT1) suspicious for clear-cell renal cell carcinoma and scheduled for nephrectomy received a single dose of [89Zr]Zr-girentuximab (37 MBq ±10%; 10 mg girentuximab) intravenously followed by abdominal PET-CT imaging 5 days (±2 days) later. Surgery was performed no later than 90 days after administration of [89Zr]Zr-girentuximab. Blinded central review, conducted by three independent readers, determined the histology from surgical samples. The coprimary endpoints, determined for each individual reader, were the sensitivity and specificity of [89Zr]Zr-girentuximab PET-CT imaging to detect clear-cell renal cell carcinoma, with histopathological confirmation as standard of truth. Analyses were on the full analysis set of patients, defined as patients who had evaluable PET-CT imaging and a confirmed histopathological diagnosis. The trial is registered with ClinicalTrials.gov, NCT03849118, and EUDRA Clinical Trials Register, 2018-002773-21, and is closed to enrolment. FINDINGS: Between Aug 14, 2019, and July 8, 2022, 371 patients were screened for eligibility, 332 of whom were enrolled. 300 patients received [89Zr]Zr-girentuximab (214 [71%] male and 86 [29%] female). 284 (95%) evaluable patients were included in the primary analysis. The mean sensitivity was 85·5% (95% CI 81·5-89·6) and mean specificity was 87·0% (81·0-93·1). No safety signals were observed. Most adverse events were not or were unlikely to be related to [89Zr]Zr-girentuximab, with most (193 [74%] of 261 events) occurring during or after surgery. The most common grade 3 or worse adverse events were post-procedural haemorrhage (in six [2%] of 261 patients), urinary retention (three [1%]), and hypertension (three [1%]). In 25 (8%) of 300 patients, 52 serious adverse events were reported, of which 51 (98%) occurred after surgery. There were no treatment-related deaths. INTERPRETATION: Our results suggest that [89Zr]Zr-girentuximab PET-CT has a favourable safety profile and is a highly accurate, non-invasive imaging modality for the detection and characterisation of clear-cell renal cell carcinoma, which has the potential to be practice changing. FUNDING: Telix Pharmaceuticals.

RESUMEN

PURPOSE: Desmoplastic small round cell tumor (DSRCT) is a rare but highly aggressive soft tissue sarcoma that arises in the abdominopelvic cavity of young males. Since the discovery of EWSR1::WT1 fusion as the driver of DSRCT, no actionable genomic alterations have been identified, limiting disease management to a combination of surgery, chemotherapy, and radiation with very poor outcomes. Herein, we leveraged ERBB2/HER2 expression in DSRCT as a therapeutic target. EXPERIMENTAL DESIGN: ERBB2/HER2 expression was evaluated in clinical samples and patient-derived xenografts (PDX) using RNA-seq, RT-qPCR, and a newly developed HER2 IHC assay (Clone 29D8). Responses to HER2 antibody-drug conjugates (ADC) -trastuzumab deruxtecan (DS-8201, T-DXd) and trastuzumab emtansine (T-DM1)- were evaluated in DSRCT-PDX, cell line, and organoid models. Drug internalization was demonstrated by live microscopy. Apoptosis was evaluated by Western blotting and caspase activity assays. RESULTS: ERBB2/HER2 was detectable in DSRCT samples from patients and PDXs, with higher sensitivity of RNA assays and improved IHC detectability using Clone 29D8. Treatment of ERBB2/HER2-expressing DSRCT PDX, cell line, and organoid models with T-DXd or T-DM1 resulted in tumor regression. This therapeutic response was long-lasting in T-DXd-treated xenografts and was mediated by rapid HER2-ADC complex internalization and cytotoxicity, triggering p53-mediated apoptosis and growth arrest. Xenograft regression was associated with bystander payload effects triggering global tumor niche responses proportional to HER2 status. Conclusions ERBB2/HER2 is a therapeutic target for DSRCT. HER2-ADCs are novel options for managing this exceptionally aggressive sarcoma and may fulfill its urgent and historically unmet need for more effective clinical therapy.

RESUMEN

Melanoma-associated antigen-A (MAGE-A) is expressed in multiple cancers with restricted expression in normal tissue. We sought to assess the MAGE-A3/A6 expression profile as well as immune landscape in urothelial (UC) and non-small cell lung carcinoma (NSCLC). We also assessed co-expression of immune-associated markers, including programmed cell death ligand 1 (PD-L1) in tumor and/or immune cells, and assessed the effect of checkpoint inhibitor treatment on these markers in the context of urothelial carcinoma. We used formalin-fixed paraffin-embedded (FFPE) tissue sections from a variety of tumor types were screened by IHC for MAGE-A and PD-L1 expression. Gene expression analyses by RNA sequencing were performed on RNA extracted from serial tissue sections. UC tumor samples from patients treated with checkpoint inhibitors were assessed by IHC and NanoString gene expression analysis for MAGE-A and immune marker expression before and after treatment. Overall, 84 samples (57%) had any detectable MAGE-A expression. Detectable MAGE-A expression was present at similar frequencies in both tumor tissue types, with 41 (50%) NSCLC and 43 (64%) UC. MAGE-A expression was not significantly changed before and after checkpoint inhibitor therapy by both IHC and NanoString mRNA sequencing. Other immune markers were similarly unchanged post immune checkpoint inhibitor therapy. Stable expression of MAGE-A3/A6 pre and post checkpoint inhibitor treatment indicates that archival specimens harvested after checkpoint therapy are applicable to screening potential candidates for MAGE therapies.

RESUMEN

RATIONALE: Uncertainty remains regarding the risks associated with single dose use of etomidate. OBJECTIVES: To assess use of etomidate in critically ill patients and compare outcomes for patients who received etomidate versus ketamine. METHODS: We assessed patients who received invasive mechanical ventilation (IMV), admitted to an ICU in the Premier Healthcare Database, 2008-2021. The exposure was receipt of etomidate on the day of IMV initiation and the main outcome was hospital mortality. Using multivariable regression we compared patients who received IMV within the first two days of hospitalization who received etomidate with propensity-score matched patients who received ketamine. We also assessed whether receipt of corticosteroids in the days after intubation modified the association between etomidate and mortality. MEASUREMENTS AND MAIN RESULTS: Of 1,689,945 patients who received IMV, nearly half (738,855; 43.7%) received etomidate. Among those who received IMV in the first two days of hospitalization, we established 22,273 matched pairs given either etomidate or ketamine. In the primary analysis, receipt of etomidate was associated with greater hospital mortality relative to ketamine (21.6% vs 18.7%; absolute risk difference: 2.8%, 95% CI 2.1%, 3.6%; adjusted odds ratio: 1.28, 95% CI 1.21,1.34). This was consistent across subgroups and sensitivity analyses. We found no attenuation of the association with mortality with receipt of corticosteroids in the days following etomidate use. CONCLUSIONS: Use of etomidate on the day of IMV initiation is common and associated with a higher odds of hospital mortality compared with ketamine. This finding is independent of subsequent treatment with corticosteroids.

RESUMEN

The hypothesis of this study was that evaluation of radiodensity assessment beyond a carotid stenosis in arterial and/or venous phase can be used to separate near-occlusion and conventional ≥ 50% stenosis. We prospectively included participants with ≥ 50% carotid stenosis with inclusion preference for cases with extracranial internal carotid artery (ICA) asymmetry. All participants were examined with a research biphasic computed tomography angiography (CTA) protocol (arterial and venous phase). Reference diagnosis was set by interpretation on CTA and radiodensity difference between ipsilateral and contralateral ICA (c-corrected) or vertebral (v-corrected) was compared. We included 93 participants, 62 with near-occlusion and 31 with conventional ≥ 50% stenosis. Just beyond the stenosis, median c-corrected radiodensity was - 20 Hounsfield units (HU) among near-occlusions and - 1 HU among conventional ≥ 50% stenoses (p < 0.001) in the arterial phase. For the venous phase, these findings were + 17 HU and + 3 HU (p = 0.007). Similar group differences were seen for v-correction. No parameter had good diagnostic performance, area under the curve ≤ 0.82. With specificity set at ≥ 95%, detected near-occlusions were foremost those with large side-to-side differences in distal ICA-diameter. Carotid near-occlusions can have reduced radiodensity beyond the stenosis in arterial phases and increased radiodensity in venous phases compared to a reference artery-which was not clearly seen for conventional stenoses. However, these radiodensity findings are best seen in near-occlusion cases that are not diagnostically challenging, while they work poorly as additional diagnostic aids.

Asunto(s)

RESUMEN

BACKGROUND: High-intensity end-of-life (EOL) care, marked by admission to intensive care units (ICUs) or in-hospital death, can be costly and burdensome. Recent trends in use of ICUs, life-sustaining treatments (LSTs), and noninvasive ventilation (NIV) during EOL hospitalizations among older adults with advanced cancer and patterns of in-hospital death are unknown. METHODS: We used SEER-Medicare data (2003-2017) to identify beneficiaries with advanced solid cancer (summary stage 7) who died within 3 years of diagnosis. We identified EOL hospitalizations (within 30 days of death), classifying them by increasing intensity of care into: (1) without ICU; (2) with ICU but without LST (invasive mechanical ventilation, tracheostomy, gastrostomy, acute dialysis) or NIV; (3) with ICU and NIV but without LST; and (4) with ICU and LST use. We constructed a multinomial regression model to evaluate trends in risk-adjusted hospitalization, overall and across hospitalization categories, adjusting for sociodemographics, cancer characteristics, comorbidities, and frailty. We evaluated trends in in-hospital death across categories. RESULTS: Of 226,263 Medicare beneficiaries with advanced cancer, 138,305 (61.1%) were hospitalized at EOL [Age, Mean (SD):77.9(7.1) years; 45.5% female]. Overall, EOL hospitalizations remained high throughout, from 78.1% (95% CI: 77.4, 78.7) in 2004 to 75.5% (95% CI: 74.5, 76.2) in 2017. Hospitalizations without ICU use decreased from 49.3% (95% CI: 48.5, 50.2) to 35.0% (95% CI: 34.2, 35.9) while hospitalizations with more intensive care increased, from 23.7% (95% CI: 23.0, 24.4) to 28.7% (95% CI: 27.9, 29.5) for ICU without LST or NIV, 0.8% (95% CI: 0.6, 0.9) to 3.8% (95% CI: 3.4, 4.1) for ICU with NIV but without LST, and 4.3% (95% CI: 4.0, 4.7) to 8.0% (95% CI: 7.5, 8.5) for ICU with LST use. Among those who experienced in-hospital death, the proportion receiving ICU care increased from 46.5% to 65.0%. CONCLUSIONS: Among older adults with advanced cancer, EOL hospitalization rates remained stable from 2004-2017. However, intensity of care during EOL hospitalizations increased as evidenced by increasing use of ICUs, LSTs, and NIV.

RESUMEN

OBJECTIVES: Hemorrhage risk assessment tools have been studied using estimated blood loss. We study the association between peripartum hemorrhage risk assessment score and peripartum quantified blood loss (QBL) in term vaginal and cesarean deliveries. METHODS: This is a retrospective analysis conducted on 3,657 patients who underwent term vaginal and cesarean deliveries at a public hospital in New York City. Utilizing the risk assessment tool developed by the Association of Women's Health, Obstetric and Neonatal Nurses (AWHONN), patients were categorized into low-, medium-, or high-risk groups for postpartum hemorrhage. RESULTS: Medium-risk (B=0.08, SE=0.01, p<0.001) and high-risk (B=0.12, SE=0.02, p<0.001) AWHONN scores were associated with significantly higher QBL as compared to low-risk AWHONN score. Medium-risk approached significance (OR: 1.67, 95 % CI: 1.00, 2.79, p=0.050) and high-risk AWHONN score was significantly associated (OR: 1.95, 95 % CI: 1.09, 3.48, p=0.02) with increased odds for postpartum hemorrhage (≥1,000 mL). Each individual factor comprising the AWHONN score whose percentage in our sample was seen in greater than 2.7 % of patients was independently significantly associated with increased QBL (six of nine factors) and postpartum hemorrhage (four of nine factors). CONCLUSIONS: The AWHONN measure previously validated with estimated blood loss predicted obstetric blood loss with QBL. Although not on the basis of the data shown in our study, we believe that QBL should be routinely used to measure obstetric blood loss.

RESUMEN

There are several well-known medical conditions in which posture and gravity interact with natural history, including pregnancy. In this review, we provide a comprehensive overview of interactions between maternal posture and maternal physiology and pathophysiology at rest during pregnancy. We conducted a systematic literature search of the MEDLINE database and identified 644 studies from 1991 through 2021, inclusive, that met our inclusion criteria. We present a narrative review of the resulting literature and highlight discrepancies, research gaps, and potential clinical implications. We organize the results by organ system and, commencing with the neurological system, proceed in our synthesis generally in the craniocaudal direction, concluding with the skin. The circulatory system warranted our greatest and closest consideration-literature concerning the dynamic interplay between physiology (heart rate, stroke volume, cardiac output, blood pressure, and systemic vascular resistance), pathophysiology (e.g., hypertension in pregnancy), and postural changes provide an intricate and fascinating example of the importance of the subject of this review. Other organ systems discussed include respiratory, renal, genitourinary, gastrointestinal, abdominal, and endocrine. In addition to summarizing the existing literature on maternal posture-physiology interactions, we also point out gaps and opportunities for further research and clinical developments in this area. Overall, our review provides both insight into and relevance of maternal posture-physiology interactions vis à vis healthcare's mission to improve health and wellness during pregnancy and beyond.

RESUMEN

BACKGROUND: There are limited opportunities to practice surgical skills and techniques in residency. Therefore, it is important to explore strategies which optimize surgical simulation experiences to enhance learning outcomes and skill retention. METHODS: Novice medical students (n = 29) were recruited to participate in a Fundamentals of Laparoscopic Surgery (FLS) peg transfer task training. Participants were randomly assigned to a control group, practicing the peg transfer task independently, or an experimental group, practicing with time pressure. Participant skill assessments were completed before the training, after the training, and 8-weeks after the training. Subjective and objective stress measurements were taken in the form of self-report surveys and heart rate variability data, respectively. RESULTS: For all the skill assessment measurements, there was no difference between groups in performance on the FLS task. Both groups showed improvement in performance after the training compared to before. The experimental group reported higher stress during and after the training period compared to the control group; however, there was no difference between groups on heart rate variability metrics. CONCLUSION: Time pressure while practicing an FLS task did not significantly impact learning acquisition or retention. However, the experimental group reported higher levels of stress. This preliminary study suggests time pressure does not confer an enhanced surgical skill learning experience for novices.

Asunto(s)

RESUMEN

Sleeping on the back after 28 weeks of pregnancy has recently been associated with giving birth to a small-for-gestational-age infant and late stillbirth, but whether a causal relationship exists is currently unknown and difficult to study prospectively. This study was conducted to build a computer vision model that can automatically detect sleeping position in pregnancy under real-world conditions. Real-world overnight video recordings were collected from an ongoing, Canada-wide, prospective, four-night, home sleep apnea study and controlled-setting video recordings were used from a previous study. Images were extracted from the videos and body positions were annotated. Five-fold cross validation was used to train, validate, and test a model using state-of-the-art deep convolutional neural networks. The dataset contained 39 pregnant participants, 13 bed partners, 12,930 images, and 47,001 annotations. The model was trained to detect pillows, twelve sleeping positions, and a sitting position in both the pregnant person and their bed partner simultaneously. The model significantly outperformed a previous similar model for the three most commonly occurring natural sleeping positions in pregnant and non-pregnant adults, with an 82-to-89% average probability of correctly detecting them and a 15-to-19% chance of failing to detect them when any one of them is present.

Asunto(s)

RESUMEN

Systemic candidiasis remains a significant public health concern worldwide, with high mortality rates despite available antifungal drugs. Drug-resistant strains add to the urgency for alternative therapies. In this context, vaccination has reemerged as a prominent immune-based strategy. Extracellular vesicles (EVs), nanosized lipid bilayer particles, carry a diverse array of native fungal antigens, including proteins, nucleic acids, lipids, and glycans. Previous studies from our laboratory demonstrated that Candida albicans EVs triggered the innate immune response, activating bone marrow-derived dendritic cells (BMDCs) and potentially acting as a bridge between innate and adaptive immunity. Vaccination with C. albicans EVs induced the production of specific antibodies, modulated cytokine production, and provided protection in immunosuppressed mice infected with lethal C. albicans inoculum. To elucidate the mechanisms underlying EV-induced immune activation, our study investigated pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs) involved in EVs-phagocyte engagement. EVs from wild-type and mutant C. albicans strains with truncated mannoproteins were compared for their ability to stimulate BMDCs. Our findings revealed that EV decoration with O- and N-linked mannans and the presence of ß-1,3-glucans and chitin oligomers may modulate the activation of specific PRRs, in particular Toll-like receptor 4 (TLR4) and dectin-1. The protective effect of vaccination with wild-type EVs was found to be dependent on TLR4. These results suggest that fungal EVs can be harnessed in vaccine formulations to selectively activate PRRs in phagocytes, offering potential avenues for combating or preventing candidiasis.IMPORTANCESystemic candidiasis is a serious global health concern with high mortality rates and growing drug resistance. Vaccination offers a promising solution. A unique approach involves using tiny lipid-coated particles called extracellular vesicles (EVs), which carry various fungal components. Previous studies found that Candida albicans EVs activate the immune response and may bridge the gap between innate and adaptive immunity. To understand this better, we investigated how these EVs activate immune cells. We demonstrated that specific components on EV surfaces, such as mannans and glucans, interact with receptors on immune cells, including Toll-like receptor 4 (TLR4) and dectin-1. Moreover, vaccinating with these EVs led to strong immune responses and full protection in mice infected with Candida. This work shows how harnessing fungal EVs might lead to effective vaccines against candidiasis.

Asunto(s)

RESUMEN

IMPORTANCE: The opioid crisis is impacting people across the country and deserves attention to be able to curb the rise in opioid-related deaths. OBJECTIVES: To evaluate practice patterns in opioid infusion administration and dosing for patients with acute respiratory failure receiving invasive mechanical ventilation. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Patients from 21 hospitals in Kaiser Permanente Northern California and 96 hospitals in Philips electronic ICU Research Institute. MAIN OUTCOMES AND MEASURES: We assessed whether patients received opioid infusion and the dose of said opioid infusion. RESULTS: We identified patients with a diagnosis of acute respiratory failure who were initiated on invasive mechanical ventilation. From each patient, we determined if opioid infusions were administered and, among those who received an opioid infusion, the median daily dose of fentanyl infusion. We used hierarchical regression models to quantify variation in opioid infusion use and the median daily dose of fentanyl equivalents across hospitals. We included 13,140 patients in the KPNC cohort and 52,033 patients in the eRI cohort. A total of 7,023 (53.4%) and 16,311 (31.1%) patients received an opioid infusion in the first 21 days of mechanical ventilation in the KPNC and eRI cohorts, respectively. After accounting for patient- and hospital-level fixed effects, the hospital that a patient was admitted to explained 7% (95% CI, 3-11%) and 39% (95% CI, 28-49%) of the variation in opioid infusion use in the KPNC and eRI cohorts, respectively. Among patients who received an opioid infusion, the median daily fentanyl equivalent dose was 692 µg (interquartile range [IQR], 129-1341 µg) in the KPNC cohort and 200 µg (IQR, 0-1050 µg) in the eRI cohort. Hospital explained 4% (95% CI, 1-7%) and 20% (95% CI, 15-26%) of the variation in median daily fentanyl equivalent dose in the KPNC and eRI cohorts, respectively. CONCLUSIONS AND RELEVANCE: In the context of efforts to limit healthcare-associated opioid exposure, our findings highlight the considerable opioid exposure that accompanies mechanical ventilation and suggest potential under and over-treatment with analgesia. Our results facilitate benchmarking of hospitals' analgesia practices against risk-adjusted averages and can be used to inform usual care control arms of analgesia and sedation clinical trials.

Asunto(s)

RESUMEN

BACKGROUND: Giant viruses have brought new insights into different aspects of virus-cell interactions. The resulting cytopathic effects from these interactions are one of the main aspects of infection assessment in a laboratory routine, mainly reflecting on the morphological features of an infected cell. OBJECTIVES: In this work, we follow the entire kinetics of the cytopathic effect in cells infected by viruses of the Mimiviridae family, spatiotemporally quantifying typical features such as cell roundness, loss of motility, decrease in cell area and cell lysis. METHODS: Infections by Acanthamoeba polyphaga mimivirus (APMV), Tupanvirus (TPV) and M4 were carried out at multiplicity of infection (MOI) 1 and MOI 10 in Acanthamoeba castellanii. Monitoring of infections was carried out using time lapse microscopy for up to 72 hours. The images were analyzed using ImageJ software. FINDINGS: The data obtained indicate that APMV is the slowest virus in inducing the cytopathic effects of rounding, decrease in cell area, mobility and cell lysis. However, it is the only virus whose MOI increase accelerates the lysis process of infected cells. In turn, TPV and M4 rapidly induce morphological and behavioral changes. MAIN CONCLUSIONS: Our results indicate that mimiviruses induce different temporal responses within the host cell and that it is possible to use these kinetic data to facilitate the understanding of infection by these viruses.

Asunto(s)

RESUMEN

BACKGROUND: Chronic inflammation may increase susceptibility to pneumonia. RESEARCH QUESTION: To explore associations between clinical comorbidities, serum protein immunoassays, and long-term pneumonia risk. METHODS: Framingham Heart Study Offspring Cohort participants ≥65 years were linked to their Centers for Medicare Services claims data. Clinical data and 88 serum protein immunoassays were evaluated for associations with 10-year incident pneumonia risk using Fine-Gray models for competing risks of death and least absolute shrinkage and selection operators for covariate selection. RESULTS: We identified 1,370 participants with immunoassays and linkage to Medicare data. During 10 years of follow up, 428 (31%) participants had a pneumonia diagnosis. Chronic pulmonary disease [subdistribution hazard ratio (SHR) 1.87; 95% confidence interval (CI), 1.33-2.61], current smoking (SHR 1.79, CI 1.31-2.45), heart failure (SHR 1.74, CI 1.10-2.74), atrial fibrillation/flutter (SHR 1.43, CI 1.06-1.93), diabetes (SHR 1.36, CI 1.05-1.75), hospitalization within one year (SHR 1.34, CI 1.09-1.65), and age (SHR 1.06 per year, CI 1.04-1.08) were associated with pneumonia. Three baseline serum protein measurements were associated with pneumonia risk independent of measured clinical factors: growth differentiation factor 15 (SHR 1.32; CI 1.02-1.69), C-reactive protein (SHR 1.16, CI 1.06-1.27) and matrix metallopeptidase 8 (SHR 1.14, CI 1.01-1.30). Addition of C-reactive protein to the clinical model improved prediction (Akaike information criterion 4950 from 4960; C-statistic of 0.64 from 0.62). CONCLUSIONS: Clinical comorbidities and serum immunoassays were predictive of pneumonia risk. C-reactive protein, a routinely-available measure of inflammation, modestly improved pneumonia risk prediction over clinical factors. Our findings support the hypothesis that prior inflammation may increase the risk of pneumonia.

Asunto(s)

RESUMEN

Objective: To describe the trajectories of linguistic, cognitive-communicative, and health-related quality of life (HRQOL) outcomes after stroke in persons with aphasia. Design: Longitudinal observational study from inpatient rehabilitation to 18 months after stroke. Setting: Four US mid-west inpatient rehabilitation facilities (IRFs). Participants: We plan to recruit 400 adult (older than 21 years) English speakers who meet the following inclusion criteria: (1) Diagnosis of aphasia after a left-hemisphere infarct confirmed by CT scan or magnetic resonance imaging (MRI); (2) first admission for inpatient rehabilitation due to a neurologic event; and (3) sufficient cognitive capacity to provide informed consent and participate in testing. Exclusion criteria include any neurologic condition other than stroke that could affect language, cognition or speech, such as Parkinson's disease, Alzheimer's disease, traumatic brain injury, or the presence of right-hemisphere lesions. Interventions: Not applicable. Main Outcome Measures: Subjects are administered a test battery of linguistic, cognitive-communicative, and HRQOL measures. Linguistic measures include the Western Aphasia Battery-Revised and the Apraxia of Speech Rating Scale. Cognitive-communicative measures include the Communication Participation Item Bank, Connor's Continuous Performance Test-3, the Communication Confidence Rating Scale for Aphasia, the Communication Effectiveness Index, the Neurological Quality of Life measurement system (Neuro-QoL) Communication short form, and the Neuro-QoL Cognitive Function short form. HRQOL measures include the 39-item Stroke & Aphasia Quality of Life Scale, Neuro-QoL Fatigue, Sleep Disturbance, Depression, Ability to Participate in Social Roles & Activities, and Satisfaction with Social Roles & Activities tests, and the Patient-Reported Outcome Measurement and Information System 10-item Global Health short form. The test battery is administered initially during inpatient rehabilitation, and at 3-, 6-, 12-, and 18-months post-IRF discharge. Biomarker samples are collected via saliva samples at admission and a subgroup of participants also undergo resting state fMRI scans. Results: Not applicable. Conclusions: This longitudinal observational study will develop trajectory models for recovery of clinically relevant linguistic, cognitive-communicative, and quality of life outcomes over 18 months after inpatient rehabilitation. Models will identify individual differences in the patterns of recovery based on variations in personal, genetic, imaging, and therapy characteristics. The resulting models will provide an unparalleled representation of recovery from aphasia resulting from stroke. This improved understanding of recovery will enable clinicians to better tailor and plan rehabilitation therapies to individual patient's needs.

RESUMEN

ALK-rearranged RCC refractory to several lines of treatment has a durable response when treated with alectinib.

Asunto(s)

RESUMEN

In numerous medical conditions, including pregnancy, gravity and posture interact to impact physiology and pathophysiology. Recent investigations, for example, pertaining to maternal sleeping posture during the third trimester and possible impact on fetal growth and stillbirth risk highlight the importance and potential clinical implications of the subject. In this review, we provide an extensive discussion of the impact of maternal posture on fetal physiology from conception to the postpartum period in human pregnancy. We conducted a systematic literature search of the MEDLINE database and identified 242 studies from 1991 through 2021, inclusive, that met our inclusion criteria. Herein, we provide a synthesis of the resulting literature. In the first section of the review, we group the results by the impact of maternal posture at rest on the cervix, uterus, placenta, umbilical cord, amniotic fluid, and fetus. In the second section of the review, we address the impact on fetal-related outcomes of maternal posture during various maternal activities (e.g., sleep, work, exercise), medical procedures (e.g., fertility, imaging, surgery), and labor and birth. We present the published literature, highlight gaps and discrepancies, and suggest future research opportunities and clinical practice changes. In sum, we anticipate that this review will shed light on the impact of maternal posture on fetal physiology in a manner that lends utility to researchers and clinicians who are working to improve maternal, fetal, and child health.

RESUMEN

A new method for the preparation of the underrepresented 1,5-dimethyl-6-thioverdazyl radicals has been developed employing Lawesson's reagent (LR). The synthetic route involves the direct thionation of the carbonyl group of the corresponding dialkylbishydrazone followed by cyclization to give the tetrazinanthione verdazyl precursor on a gram scale. Subsequent oxidation yields the 6-thioverdazyl radical. It was determined that thionation of substrates containing electron-withdrawing groups in the ortho- or para-positions was high yielding. In contrast, for the parent phenyl group or substrates bearing weakly electron-donating substituents, thionation efficiency was significantly reduced. This could be overcome by utilizing partial in situ cyclization, which occurs during work up, to generate the tetrazinanthione directly via a one-pot synthesis. Density functional theory suggests that the LR fragment interacts with the carbonyl prior to cycloaddition and subsequent to cycloreversion, leading to the thiocarbonyl. The electronic nature of the radical is characterized with electron paramagnetic resonance as well as the first report of 6-thioverdazyl redox properties.