•Few data on neurologic outcomes after in utero exposure to general anesthesia (GA).•Secondary analysis of randomized trial of maternal magnesium and cerebral palsy.•Exposure to GA was not associated ...with impaired neurodevelopment overall.•Only severe motor delay was significantly more common among infants exposed to GA.•Findings are reassuring regarding a single, short in utero exposure to GA.
In 2016, the U.S. Food and Drug Administration expressed concern that neurodevelopment may be negatively affected by anesthesia or sedation exposure in pregnancy or before three years of age. We examined the association between general anesthesia at the time of cesarean delivery and early childhood neurodevelopment.
A secondary analysis of a multicenter randomized controlled trial assessing magnesium for prevention of cerebral palsy in infants at risk for preterm delivery. Exposure was general compared to neuraxial anesthesia. The primary outcome was motor or mental delay at two years of age, assessed by Bayley Scales of Infant Development II (BSIDII). Secondary outcomes included BSIDII subdomains and perinatal outcomes. Multivariable logistic regression models were performed to control for confounders.
Of 557 women undergoing cesarean delivery, 119 (21%) received general anesthesia. There were no differences in the primary composite outcome of developmental delay (aOR 0.93, 95% CI 0.61 to 1.43) or the BSIDII subdomains of mild, moderate, or severe mental delay, or mild or moderate motor delay. Severe motor delay was more common among infants exposed to general anesthesia (aOR 1.98, 95% CI 1.06 to 3.69). Infants exposed to general anesthesia had longer neonatal intensive care stays (51 vs 37 days, P=0.010).
General anesthesia for cesarean delivery was not associated with overall neurodevelopmental delay at two years of age, except for greater odds of severe motor delay. Future studies should evaluate this finding, as well as the impact on neurodevelopment of longer or multiple anesthetic exposures across all gestational ages.
The crystal structure of the G‐rich human telomeric DNA Tel22 has been determined at 1.35 Å resolution in space group P6. Tel22 forms a non‐canonical DNA structure called the G‐quadruplex. The space ...group and unit‐cell parameters are comparable to those in the crystal structures with PDB codes 6ip3 (1.40 Å resolution) and 1kf1 (2.15 Å resolution). The G‐quadruplexes are highly similar in all of the structures. However, this structure of Tel22 displays clear density for polyethylene glycol and two potassium ions, which are located outside the ion channel in the G‐quadruplex and play an important role in stabilizing the crystal contacts. In addition, 111 water molecules were identified (compared with 79 and 68 in PDB entries 6ip3 and 1kf1, respectively) that participate in intricate and extensive networks providing high stability to the G‐quadruplex.
The crystal structure of the G‐rich human telomeric DNA Tel22 has been determined at 1.35 Å resolution. The structure contains a three‐tetrad parallel G‐quadruplex (GQ) that forms a 5′–5′ dimer with a symmetry‐generated molecule and is stabilized by five potassium ions. The solvent sphere contains polyethylene glycol, two potassium ions and 111 water molecules. The presence of polyethylene glycol is significant as it has been shown to stabilize the parallel GQ conformation, yet its mechanism of interaction with a parallel GQ is not fully understood.
Objectives
Worldwide, depression is one of the most common medical disorders in adolescence. Adolescent depressive symptoms generally increase over time, but many experience decreases after an ...initial peak. The purpose of this paper was to examine ecological predictors of baseline and change in adolescent depressive symptoms using Maslow’s Hierarchy of Needs as a framework.
Methods
Adolescents (
n
= 500; 52% female; baseline age 10–13 years) and their parents living in the northwestern United States completed annual questionnaires over six years. A structural equation model growth curve analysis was conducted to examine how family stressors, neighborhood safety, parent-child connectedness, and youth locus of control predicted adolescent depressive symptoms (baseline and growth).
Results
Results demonstrated that adolescent locus of control was associated with lower baseline depressive symptoms (
β
= −0.27,
p
< 0.001). Parent-child connectedness (youth-report) was indirectly predictive of baseline depressive symptoms through locus of control (
β
= −0.06,
p
< 0.05). Family economic stress was predictive of less growth in depressive symptoms over time (
β
= −0.20,
p
< 0.05). General family stressors, neighborhood safety, and parent report of parent-child connectedness were not predictive of adolescent depressive symptoms. In a sensitivity analysis using an autoregressive model, adolescent-report of parent-child connectedness was the most consistently predictive measure of adolescent depressive symptoms.
Conclusions
Overall, the results suggest that feelings of family connectedness and control are more important to understanding baseline depressive symptoms than physical, contextual factors. However, some adversity may be healthy and provide adolescents with experiences that slow the growth of depression.
To define the impact of care standardization on caffeine and cardiorespiratory monitoring at neonatal intensive care unit (NICU) discharge.
Electronic records were abstracted for infants aged 24-36 ...weeks gestation with birth weights appropriate for gestational age. Infants who died, transferred prior to discharge, had major pulmonary anomalies, required a home monitor for mechanical ventilation or had a family history of sudden infant death syndrome were excluded. Data and records were used to indicate when the new definition of clinically significant cardiopulmonary events (CSCPEs) and concurrent education was implemented. Preimplementation and postimplementation cohorts were compared.
Incidence fell from 74% diagnosed with apnea of prematurity at baseline to 49% diagnosed with CSCPE postimplementation (P<0.001). Infants discharged on caffeine reduced from 17% to 5% (P<0.001), and home monitor use also fell from 54% to 16% (P<0.001).
Standardizing definitions and treatments reduced the use of caffeine and cardiorespiratory monitors upon NICU dismissal.
To evaluate pain, swallowing, speech, edematous response, tissue shrinkage, sleep, snoring, and safety (energy limits and adverse effects) following radiofrequency (RF) treatment to the palate in 22 ...subjects with sleep-disordered breathing.
This investigation is a prospective nonrandomized study. Polysomnography, radiographic imaging, and infrared thermography, along with questionnaires and visual analog scales, were used to evaluate the effects of RF treatment to the palate.
Treatments were delivered on an outpatient basis at Stanford University Medical Center.
Twenty-two healthy patients (18 men), with a mean age of 45.3±9.1 years, were enrolled. All were snorers seeking treatment and met predetermined criteria: a respiratory disturbance index ≤15, oxygen saturation ≥85%, and a complaint of daytime sleepiness.
RF was delivered to the submucosa of the palate with a custom-fabricated electrode for a mean duration of 141 ±30 s with a mean of 3.6±1.2 treatments per patient. Reduction of their snoring scores determined the end point of the study.
Neither speech nor swallowing was adversely affected. Pain was of short duration (0 to 48 h) and was controlled with acetaminophen. There were no infections. Although there was documented edema at 24 to 48 h, there were no clinical airway compromises. Polysomnographic data showed improvement in esophageal pressure measurements of the mean nadir and the 95th percentile nadir (p=0.031, p=0.001) respectively, as well as the mean sleep efficiency index (p=0.002). Radiographic imaging showed a mean shrinkage of 5.5±3.7 mm (p≤0.0001). Subjective snoring scores fell by a mean of 77% (8.3±1.8 to 1.9±1.7, p=0.0001) accompanied by improved mean Epworth sleepiness scores (8.5±4.4 to 5.2±3.3, p=0.0001).
The results of this investigation allowed the formulation of safety parameters for RF in this defined population with mild sleep-disordered breathing. There was a documented tissue reduction and improvement in symptoms in all subjects. However, given the small sample size and short-term follow-up, these results should be confirmed by further investigation.
Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, ...whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumours. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumours of DLBCL patients, apparently reflecting the variation in tumour proliferation rate, host response and differentiation state of the tumour. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal centre B cells ('germinal centre B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal centre B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumours on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
The objective was to examine the relationship between patient uncertainty at the time of emergency department (ED) discharge as measured by the “Uncertainty Scale” (U‐Scale) and 30‐day ...return ED visits. We hypothesized that a higher score on the U‐Scale predicts a higher likelihood of a 30‐day return ED visit.
Methods
This was a cross‐sectional single‐site pilot study performed with adult patients discharged from an urban academic ED to assess the relationship of U‐Scale total and subscale scores with 30‐day return ED visits. We collected demographic and U‐Scale scores at the time of ED discharge and subsequent 30‐day ED utilization data by follow‐up telephone call.
Results
No association was found between the total U‐Scale score and subsequent ED utilization. Patients with higher uncertainty on the Treatment Quality subscale of the U‐Scale had higher odds of a 30‐day return ED visit (adjusted odds ratio AOR = 1.16), while patients with lower uncertainty on the Decision to Seek Care subscale had higher odds of a 30‐day return ED visit (AOR = 0.68).
Conclusion
Patient uncertainty as measured by the U‐Scale total score was not predictive of subsequent ED utilization. However, uncertainty related to treatment quality and the decision to seek care as measured by the U‐Scale subscales may be important in predicting repeat ED utilization. Unlike individual patient factors such as age and race that have been associated with frequent ED visits in prior studies, these domains of uncertainty are potentially modifiable. Providers and health systems may successfully prevent recurrent acute care encounters through implementation of interventions designed to address patient uncertainty. Further work is needed to refine the U‐Scale and test its predictive utility among a larger patient cohort.
This review is focused on mouse models for prostate cancer that have been designed on the basis of genetic alterations that are frequently found in human prostate cancer. It begins with an analysis ...of the similarities and differences in the gross and microscopic anatomy of the mouse and human prostate glands, and extends to the pathologies induced in the genetically manipulated mouse prostate in comparison with the sporadic development of the disease in humans. Major achievements have been made in modeling human prostate cancer in mice in recent years. There are models which display slow, temporal development of increasingly severe preneoplastic lesions, which are remarkably restricted to the prostate gland, a property similar to the aging-related progression of these lesions in humans. Other models rapidly progress to local invasive adenocarcinoma, and, in some of them metastasis is manifested subsequently with defined kinetics. Global assessment of molecular changes in the prostate of the genetically manipulated mice is increasingly underscoring the validity of the models through identification of 'signature' genes which are associated with the organ-confined primary or distant metastases of human prostate cancer. Taken together, various 'natural' models depicting stages of the disease, ranging from the early preneoplastic lesions to metastatic prostate cancer, now provide new tools both for exploring the molecular mechanism underlying prostate cancer and for development or testing of new targeted therapies.
Higher levels of institutional trust have been associated with increased preventive healthcare use, greater adherence to treatment plans, and improved overall self-rated health status. However, ...little attention has been paid to understanding approaches to improve patient institutional trust. This study used group concept mapping to elicit patient perspectives on ways to improve patient trust. Eighteen insured individuals living in Delaware County, Pennsylvania, participated in the concept mapping sessions. Participants first brainstormed in a group setting to develop a list of ideas about how systems could improve trust, then each participant sorted the ideas into thematic domains and rated the statements based on both importance and feasibility. Four primary domains for improving institutional trust emerged: privacy, patient-provider relationship, respect for patients, and health system guidelines. Multiple action items to improve patient trust of the system were provided for each domain, and participants rated the "privacy" domain as the most feasible and important to address.We suggest that future local efforts to build institutional trust implement processes to improve the protection of patient privacy, support patient-provider relationships, and engender respect for patients, and that institutions develop system-level guidelines to support these principles. Next steps involve exploring the importance of these domains across other populations and developing and testing targeted interventions.
Endometrial cancer can be molecularly classified into POLEmut, mismatch repair deficient (MMRd), p53 abnormal (p53abn), and no specific molecular profile (NSMP) subgroups. We aimed to develop an ...interpretable deep learning pipeline for whole-slide-image-based prediction of the four molecular classes in endometrial cancer (im4MEC), to identify morpho-molecular correlates, and to refine prognostication.
This combined analysis included diagnostic haematoxylin and eosin-stained slides and molecular and clinicopathological data from 2028 patients with intermediate-to-high-risk endometrial cancer from the PORTEC-1 (n=466), PORTEC-2 (n=375), and PORTEC-3 (n=393) randomised trials and the TransPORTEC pilot study (n=110), the Medisch Spectrum Twente cohort (n=242), a case series of patients with POLEmut endometrial cancer in the Leiden Endometrial Cancer Repository (n=47), and The Cancer Genome Atlas-Uterine Corpus Endometrial Carcinoma cohort (n=395). PORTEC-3 was held out as an independent test set and a four-fold cross validation was performed. Performance was measured with the macro and class-wise area under the receiver operating characteristic curve (AUROC). Whole-slide images were segmented into tiles of 360 μm resized to 224 × 224 pixels. im4MEC was trained to learn tile-level morphological features with self-supervised learning and to molecularly classify whole-slide images with an attention mechanism. The top 20 tiles with the highest attention scores were reviewed to identify morpho-molecular correlates. Predictions of a nuclear classification deep learning model serve to derive interpretable morphological features. We analysed 5-year recurrence-free survival and explored prognostic refinement by molecular class using the Kaplan-Meier method.
im4MEC attained macro-average AUROCs of 0·874 (95% CI 0·856–0·893) on four-fold cross-validation and 0·876 on the independent test set. The class-wise AUROCs were 0·849 for POLEmut (n=51), 0·844 for MMRd (n=134), 0·883 for NSMP (n=120), and 0·928 for p53abn (n=88). POLEmut and MMRd tiles had a high density of lymphocytes, p53abn tiles had strong nuclear atypia, and the morphology of POLEmut and MMRd endometrial cancer overlapped. im4MEC highlighted a low tumour-to-stroma ratio as a potentially novel characteristic feature of the NSMP class. 5-year recurrence-free survival was significantly different between im4MEC predicted molecular classes in PORTEC-3 (log-rank p<0·0001). The ten patients with aggressive p53abn endometrial cancer that was predicted as MMRd showed inflammatory morphology and appeared to have a better prognosis than patients with correctly predicted p53abn endometrial cancer (p=0·30). The four patients with NSMP endometrial cancer that was predicted as p53abn showed higher nuclear atypia and appeared to have a worse prognosis than patients with correctly predicted NSMP (p=0·13). Patients with MMRd endometrial cancer predicted as POLEmut had an excellent prognosis, as do those with true POLEmut endometrial cancer.
We present the first interpretable deep learning model, im4MEC, for haematoxylin and eosin-based prediction of molecular endometrial cancer classification. im4MEC robustly identified morpho-molecular correlates and could enable further prognostic refinement of patients with endometrial cancer.
The Hanarth Foundation, the Promedica Foundation, and the Swiss Federal Institutes of Technology.
