The frailty index is a known predictor of adverse outcomes in geriatric patients. Trauma-Specific Frailty Index (TSFI) was created and validated at a single center to accurately identify frailty and ...reliably predict worse outcomes among geriatric trauma patients. This study aims to prospectively validate the TSFI in a multi-institutional cohort of geriatric trauma patients.
This is a prospective, observational, multi-institutional trial across 17 American College of Surgeons Levels I, II, and III trauma centers. All geriatric trauma patients (65 years and older) presenting during a 3-year period were included. Frailty status was measured within 24 hours of admission using the TSFI (15 variables), and patients were stratified into nonfrail (TSFI, ≤0.12), prefrail (TSFI, 0.13-0.25), and frail (TSFI, >0.25) groups. Outcome measures included index admission mortality, discharge to rehabilitation centers or skilled nursing facilities (rehab/SNFs), and 3-month postdischarge readmissions, fall recurrences, complications, and mortality among survivors of index admission.
A total of 1,321 geriatric trauma patients were identified and enrolled for validation of TSFI (nonfrail, 435 33%; prefrail, 392 30%; frail, 494 37%). The mean ± SD age was 77 ± 8 years; the median (interquartile range) Injury Severity Score was 9 (5-13). Overall, 179 patients (14%) had a major complication, 554 (42%) were discharged to rehab/SNFs, and 63 (5%) died during the index admission. Compared with nonfrail patients, frail patients had significantly higher odds of mortality (adjusted odds ratio aOR, 1.93; p = 0.018), major complications (aOR, 3.55; p < 0.001), and discharge to rehab/SNFs (aOR, 1.98; p < 0.001). In addition, frailty was significantly associated with higher adjusted odds of mortality, major complications, readmissions, and fall recurrence at 3 months postdischarge ( p < 0.05).
External applicability of the TSFI (15 variables) was evident at a multicenter cohort of 17 American College of Surgeons trauma centers in geriatric trauma patients. The TSFI emerged as an independent predictor of worse outcomes, both in the short-term and 3-month postdischarge.
Prognostic and Epidemiological; Level III.
An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic ...staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies e.g., Alzheimer’s disease neuropathologic changes (ADNC) and Lewy body disease. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.
The tumour stroma is believed to contribute to some of the most malignant characteristics of epithelial tumours. However, signalling between stromal and tumour cells is complex and remains poorly ...understood. Here we show that the genetic inactivation of Pten in stromal fibroblasts of mouse mammary glands accelerated the initiation, progression and malignant transformation of mammary epithelial tumours. This was associated with the massive remodelling of the extracellular matrix (ECM), innate immune cell infiltration and increased angiogenesis. Loss of Pten in stromal fibroblasts led to increased expression, phosphorylation (T72) and recruitment of Ets2 to target promoters known to be involved in these processes. Remarkably, Ets2 inactivation in Pten stroma-deleted tumours ameliorated disruption of the tumour microenvironment and was sufficient to decrease tumour growth and progression. Global gene expression profiling of mammary stromal cells identified a Pten-specific signature that was highly represented in the tumour stroma of patients with breast cancer. These findings identify the Pten-Ets2 axis as a critical stroma-specific signalling pathway that suppresses mammary epithelial tumours.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background The relationships of working hours and nights on call per week with various parameters of distress among practicing surgeons have not been previously examined in detail. Study Design More ...than 7,900 members of the American College of Surgeons responded to an anonymous, cross-sectional survey. The survey included self-assessment of their practice setting, a validated depression screening tool, and standardized assessments of burnout and quality of life. Results There was a clear gradient between hours and burnout, with the prevalence of burnout ranging from 30% for surgeons working <60 hours/week, 44% for 60 to 80 hours/week, and 50% for those working >80 hours/week (p < 0.001). When correlated with number of nights on call, burnout exhibited a threshold effect at ≥2 nights on call/week (≤1 nights on call/week, 30%; ≥2 nights on call/week, 44% to 46%; p < 0.0001). Screening positive for depression rate also correlated strongly with hours and nights on call (both p < 0.0001). Those who worked >80 hours/week reported a higher rate of medical errors compared with those who worked <60 hours/week (10.7% versus 6.9%; p < 0.001), and were twice as likely to attribute the error to burnout (20.1% versus 8.9%; p = 0.001). Not surprisingly, work and home conflicts were higher among surgeons who worked longer hours or had ≥2 nights on call. A significantly higher proportion of surgeons who worked >80 hours/week or had >2 nights on call/week would not become a surgeon again (p < 0.0001). Conclusions Number of hours worked and nights on call per week appear to have a substantial impact on surgeons, both professionally and personally. These factors are strongly related to burnout, depression, career satisfaction, and work and home conflicts.
Suicide rates for adolescents and young adults (AYA) have risen dramatically in recent years – by almost 60% for Americans aged 10–24 years between 2007 and 2018. This increase has occurred for both ...whites and Blacks, with the rise in suicide among Black youth of particular note. Blacks historically exhibit lower rates of suicide relative to whites and thus, less is known about the etiology of Black suicide. To gain insight into the underlying causes of suicide among AYA, we examine medical examiner reports from the National Violent Death Reporting System (NVDRS) from 2013 to 2019 for over 26,000 Black and white suicide decedents ages 10–29. We apply structural topic modeling (STM) approaches to describe the broad contours of AYA suicide in the United States today. Our findings reveal distinct patterns by race. Guns, violence and the criminal justice system are prominent features of Black suicide, whether through the mechanism used in the suicide, either by firearm or other violent means such as fire or electrocution, the existence of criminal or legal problems/disputes, the location of death in a jail, or the presence of police. In contrast, the narratives of white AYA are more likely to reference mental health or substance abuse problems. Access to resources, as measured by county median household income, overlay these patterns. Themes more prevalent among Blacks are more common in poorer counties; those more prevalent among whites tend to be more common in wealthier counties. Our findings are consistent with other studies that suggest Black people experience greater exposure to violence and other traumas, systemic racism and interpersonal discrimination that may elevate the risk for suicidal behavior.
•Latent themes in the narratives of Black and white suicide decedents aged 10–29 years are examined.•Guns, violence, and the criminal justice system are prominent features of Black suicide.•White suicide is more likely to be characterized by mental health or substance abuse problems.•Access to resources, as measured by county median household income, overlay these patterns.•Suicide prevention efforts must be culturally informed.
OBJECTIVE:To determine the number of total thyroidectomies per surgeon per year associated with the lowest risk of complications.
BACKGROUND:The surgeon volume–outcome association has been ...established for thyroidectomy; however, a threshold number of cases defining a “high-volume” surgeon remains unclear.
METHODS:Adults undergoing total thyroidectomy were identified from the Health Care Utilization Project-National Inpatient Sample (1998–2009). Multivariate logistic regression with restricted cubic splines was utilized to examine the association between the number of annual total thyroidectomies per surgeon and risk of complications.
RESULTS:Among 16,954 patients undergoing total thyroidectomy, 47% had thyroid cancer and 53% benign disease. Median annual surgeon volume was 7 cases; 51% of surgeons performed 1 case/y. Overall, 6% of the patients experienced complications. After adjustment, the likelihood of experiencing a complication decreased with increasing surgeon volume up to 26 cases/y (P < 0.01). Among all patients, 81% had surgery by low-volume surgeons (≤25 cases/y). With adjustment, patients undergoing surgery by low-volume surgeons were more likely to experience complications (odds ratio 1.51, P = 0.002) and longer hospital stays (+12%, P = 0.006). Patients had an 87% increase in the odds of having a complication if the surgeon performed 1 case/y, 68% for 2 to 5 cases/y, 42% for 6 to 10 cases/y, 22% for 11 to 15 cases/y, 10% for 16 to 20 cases/y, and 3% for 21 to 25 cases/y.
CONCLUSIONS:This is the first study to identify a surgeon volume threshold (>25 total thyroidectomies/y) that is associated with improved patient outcomes. Identifying a threshold number of cases defining a high-volume thyroid surgeon is important, as it has implications for quality improvement, criteria for referral and reimbursement, and surgical education.
To determine the number of total thyroidectomies per surgeon per year associated with the lowest risk of complications.
The surgeon volume-outcome association has been established for thyroidectomy; ...however, a threshold number of cases defining a "high-volume" surgeon remains unclear.
Adults undergoing total thyroidectomy were identified from the Health Care Utilization Project-National Inpatient Sample (1998-2009). Multivariate logistic regression with restricted cubic splines was utilized to examine the association between the number of annual total thyroidectomies per surgeon and risk of complications.
Among 16,954 patients undergoing total thyroidectomy, 47% had thyroid cancer and 53% benign disease. Median annual surgeon volume was 7 cases; 51% of surgeons performed 1 case/y. Overall, 6% of the patients experienced complications. After adjustment, the likelihood of experiencing a complication decreased with increasing surgeon volume up to 26 cases/y (P < 0.01). Among all patients, 81% had surgery by low-volume surgeons (≤25 cases/y). With adjustment, patients undergoing surgery by low-volume surgeons were more likely to experience complications (odds ratio 1.51, P = 0.002) and longer hospital stays (+12%, P = 0.006). Patients had an 87% increase in the odds of having a complication if the surgeon performed 1 case/y, 68% for 2 to 5 cases/y, 42% for 6 to 10 cases/y, 22% for 11 to 15 cases/y, 10% for 16 to 20 cases/y, and 3% for 21 to 25 cases/y.
This is the first study to identify a surgeon volume threshold (>25 total thyroidectomies/y) that is associated with improved patient outcomes. Identifying a threshold number of cases defining a high-volume thyroid surgeon is important, as it has implications for quality improvement, criteria for referral and reimbursement, and surgical education.
We recently reported that Inosine Monophosphate Dehydrogenase (IMPDH), a rate-limiting enzyme in de novo guanine nucleotide biosynthesis, clustered into macrostructures in response to decreased ...nucleotide levels and that there were differences between the IMPDH isoforms, IMPDH1 and IMPDH2. We hypothesised that the Bateman domains, which are present in both isoforms and serve as energy-sensing/allosteric modules in unrelated proteins, would contribute to isoform-specific differences and that mutations situated in and around this domain in IMPDH1 which give rise to retinitis pigmentosa (RP) would compromise regulation. We employed immuno-electron microscopy to investigate the ultrastructure of IMPDH macrostructures and live-cell imaging to follow clustering of an IMPDH2-GFP chimera in real-time. Using a series of IMPDH1/IMPDH2 chimera we demonstrated that the propensity to cluster was conferred by the N-terminal 244 amino acids, which includes the Bateman domain. A protease protection assay suggested isoform-specific purine nucleotide binding characteristics, with ATP protecting IMPDH1 and AMP protecting IMPDH2, via a mechanism involving conformational changes upon nucleotide binding to the Bateman domain without affecting IMPDH catalytic activity. ATP binding to IMPDH1 was confirmed in a nucleotide binding assay. The RP-causing mutation, R224P, abolished ATP binding and nucleotide protection and this correlated with an altered propensity to cluster. Collectively these data demonstrate that (i) the isoforms are differentially regulated by AMP and ATP by a mechanism involving the Bateman domain, (ii) communication occurs between the Bateman and catalytic domains and (iii) the RP-causing mutations compromise such regulation. These findings support the idea that the IMPDH isoforms are subject to distinct regulation and that regulatory defects contribute to human disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
β-blockers are among the most widely prescribed of all drugs, used for treatment of a large number of cardiovascular diseases. Herein we evaluate literature pertaining to pharmacogenetics of ...β-blocker therapy, provide insight into the robustness of the genetic associations, and determine the appropriateness for translating these genetic associations into clinical practice.
A literature search was conducted using PubMed to collate evidence on associations between CYP2D6, ADRB1, ADRB2, and GRK5 genetic variation and drug-response outcomes in the presence of β-blocker exposure. Pharmacokinetic, pharmacodynamic, and clinical outcomes studies were included if genotype data and β-blocker exposure were documented.
Substantial data suggest that specific ADRB1 and GRK5 genotypes are associated with improved β-blocker efficacy and have potential for use to guide therapy decisions in the clinical setting. While the data do not justify ordering a CYP2D6 pharmacogenetic test, if CYP2D6 genotype is available in the electronic health record, there may be clinical utility for understanding dosing of β-blockers.
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