Evaluating and Enhancing Nursing Caregiver Well-being Using a Systematic Approach.

OBJECTIVE: The aims of this study were to evaluate nursing caregiver well-being and identify interventions for improving well-being and practice environments. BACKGROUND: Healthcare worker well-being and burnout command increasing attention in the wake of the pandemic. Experts recommend utilization of validated measurements to assess burnout, well-being, and contributing factors. METHODS: Using a descriptive, cross-sectional, mixed-methods study design, an online survey, which included the Professional Quality of Life-5, Meaning and Joy in Work Questionnaire, and open-ended questions, was administered to nurses and unlicensed assistive caregivers in an academic health system. RESULTS: Caregivers reported moderate compassion satisfaction, low burnout and compassion fatigue, and low-moderate levels of meaning and joy in work. Overall and subscale scores varied primarily based on age, experience, and role. Top causes of stress and recommendations for improvement were identified. CONCLUSION: The levels of meaning and joy in work among nursing caregivers continue to be of concern for organizational leaders. The engagement of nurses and other caregiver team members in a systematic mixed-methods approach, including using validated tools to evaluate caregiver well-being, can lead to meaningful, data-driven action planning to promote well-being and increase the meaning and joy of the work they perform.

Diverse presentations of Cushing's syndrome during pregnancy - A case series.

BACKGROUND: Cushing's syndrome (CS) encompasses various causes of hypercortisolism including adrenocorticotropic hormone (ACTH) secreting pituitary adenoma with or without bilateral adrenal hyperplasia, an adrenal adenoma or carcinoma, ectopic ACTH or corticotrophin-releasing hormone (CRH) secretion by a neoplasm or exogenous corticosteroid therapy. The diagnosis of CS in pregnancy presents a challenge due to overlapping clinical features of pregnancy (weight gain, striae, acne). If untreated, CS in pregnancy is associated with increased risk of maternal and fetal complications. AIMS: With fewer than 250 cases currently published, we aim to review the clinical presentations, diagnostic methods, management, and outcomes of patients with CS in pregnancy to help optimise our clinical practice. MATERIALS AND METHODS: This is a single-centre, retrospective review of woman with documented hypercortisolism receiving antenatal care at a tertiary maternity hospital in Perth between 2006 to 2022. Data were collated from electronic and chart reviews. OMNI calculator was used for birthweight calculations. Local ethics and patient consent were obtained. RESULTS: Five women and seven pregnancies were identified. Four women had a pituitary source of ACTH-dependent CS as confirmed by brain magnetic resonance imaging. One woman had an ectopic source of ACTH. Two women were diagnosed during pregnancy. All pregnancies occurring prior to treatment of the Cushing's disease were complicated by secondary hypertension and diabetes. CONCLUSION: CS represents a rare and difficult to diagnose condition in pregnancy. When untreated, maternal and fetal outcomes are compromised. Close monitoring of the associated complications with involvement of a multidisciplinary team are recommended.

Salicylates enhance CRM1 inhibitor antitumor activity by induction of S-phase arrest and impairment of DNA-damage repair.

Chromosome region maintenance protein 1 (CRM1) mediates protein export from the nucleus and is a new target for anticancer therapeutics. Broader application of KPT-330 (selinexor), a first-in-class CRM1 inhibitor recently approved for relapsed multiple myeloma and diffuse large B-cell lymphoma, have been limited by substantial toxicity. We discovered that salicylates markedly enhance the antitumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. Using salicylates in combination enables targeting of a range of blood cancers with a much lower dose of selinexor, thereby potentially mitigating prohibitive clinical adverse effects. Choline salicylate (CS) with low-dose KPT-330 (K+CS) had potent, broad activity across high-risk hematological malignancies and solid-organ cancers ex vivo and in vivo. The K+CS combination was not toxic to nonmalignant cells as compared with malignant cells and was safe without inducing toxicity to normal organs in mice. Mechanistically, compared with KPT-330 alone, K+CS suppresses the expression of CRM1, Rad51, and thymidylate synthase proteins, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, cell-cycle arrest in S-phase, and cell apoptosis. Moreover, the addition of poly (ADP-ribose) polymerase inhibitors further potentiates the K+CS antitumor effect. K+CS represents a new class of therapy for multiple types of blood cancers and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for cancer therapy in general.

Thalamic deep brain stimulation paradigm to reduce consciousness: Cortico-striatal dynamics implicated in mechanisms of consciousness.

Anesthetic manipulations provide much-needed causal evidence for neural correlates of consciousness, but non-specific drug effects complicate their interpretation. Evidence suggests that thalamic deep brain stimulation (DBS) can either increase or decrease consciousness, depending on the stimulation target and parameters. The putative role of the central lateral thalamus (CL) in consciousness makes it an ideal DBS target to manipulate circuit-level mechanisms in cortico-striato-thalamic (CST) systems, thereby influencing consciousness and related processes. We used multi-microelectrode DBS targeted to CL in macaques while recording from frontal, parietal, and striatal regions. DBS induced episodes of abnormally long, vacant staring with low-frequency oscillations here termed vacant, perturbed consciousness (VPC). DBS modulated VPC likelihood in a frequency-specific manner. VPC events corresponded to decreases in measures of neural complexity (entropy) and integration (Φ*), proposed indices of consciousness, and substantial changes to communication in CST circuits. During VPC, power spectral density and coherence at low frequencies increased across CST circuits, especially in thalamo-parietal and cortico-striatal pathways. Decreased consciousness and neural integration corresponded to shifts in cortico-striatal network configurations that dissociated parietal and subcortical structures. Overall, the features of VPC and implicated networks were similar to those of absence epilepsy. As this same multi-microelectrode DBS method-but at different stimulation frequencies-can also increase consciousness in anesthetized macaques, it can be used to flexibly address questions of consciousness with limited confounds, as well as inform clinical investigations of other consciousness disorders.

Haemodialysis vascular catheter-related blood stream infection: Organism types and clinical outcomes.

Catheter-related bloodstream infection (CRBI) is an important complication of catheter use for haemodialysis, but it remains unclear whether clinical outcomes following CRBI are influenced by organism type. This study aims to compare clinical outcomes following CRBI from Gram-positive and non-Gram-positive organisms. This was a retrospective cohort study of patients with kidney failure receiving haemodialysis (HD) via vascular catheters who had a documented episode of CRBI in Western Australia between 2005 and 2018. The associations between organism type, likelihood of hospitalization, catheter removal and death from CRBI were examined using adjusted logistic regression models. There were 111 episodes of CRBI in 99 patients (6.1 episodes per 1000-catheter-days at risk). Of the study cohort, 53 (48%) were male and 38 (34%) identified as Aboriginal or Torres Strait Islander. Gram-positive organisms were identified in 73 (66%) CRBI episodes, most commonly Staphylococcus aureus. Of those with non-Gram-positive CRBI, 9 (24%) were attributed to Pseudomonas aeruginosa. One-hundred and two (92%) episodes of CRBI required hospitalization and 15 (13%) patients died from CRBI. Compared with non-Gram-positive CRBI, Gram-positive CRBI was associated with an increased risk of hospitalization and catheter removal, with adjusted odds ratio of 9.34 (95% CI 1.28-68.03) and 3.47 (95% CI 1.25-9.67), respectively. There was no association between organism type and death from CRBI. Staphylococcus aureus remains the most common organism causing CRBI in HD patients. CRBI is associated with substantial morbidity, particularly CRBI attributed to Gram-positive organisms.

Does Individualization of Cup Position Affect Prosthetic or Bone Impingement Following Total Hip Arthroplasty?

BACKGROUND: Spinopelvic (SP) mobility patterns during postural changes affect three-dimensional acetabular component position, the incidence of prosthetic impingement, and total hip arthroplasty (THA) instability. Surgeons have commonly placed the acetabular component in a similar "safe zone" for most patients. Our purpose was to determine the incidence of bone and prosthetic impingement with various cup orientations and determine if a preoperative SP analysis with individualized cup orientation lessens impingement. METHODS: A preoperative SP evaluation of 78 THA subjects was performed. Data were analyzed using a software program to determine the prevalence of prosthetic and bone impingement with a patient individualized cup orientation versus 6 commonly selected cup orientations. Impingement was correlated with known SP risk factors for dislocation. RESULTS: Prosthetic impingement was least with the individualized choice of cup position (9%) versus preselected cup positions (18%-61%). The presence of bone impingement (33%) was similar in all groups and not affected by cup position. Factors associated with impingement in flexion were age, lumbar flexion, pelvic tilt (stand to flexed seated), and functional femoral stem anteversion. Risk factors in extension included standing pelvic tilt, standing SP tilt, lumbar flexion, pelvic rotation (supine to stand and stand to flexed seated), and functional femoral stem anteversion. CONCLUSION: Prosthetic impingement is reduced with individualized cup positioning based on SP mobility patterns. Bone impingement occurred in one-third of patients and is a noteworthy consideration in preoperative THA planning. Known SP risk factors for THA instability correlated with the presence of prosthetic impingement in both flexion and extension.

Predictive Feedback, Early Sensory Representations, and Fast Responses to Predicted Stimuli Depend on NMDA Receptors.

Learned associations between stimuli allow us to model the world and make predictions, crucial for efficient behavior (e.g., hearing a siren, we expect to see an ambulance and quickly make way). While there are theoretical and computational frameworks for prediction, the circuit and receptor-level mechanisms are unclear. Using high-density EEG, Bayesian modeling, and machine learning, we show that inferred "causal" relationships between stimuli and frontal alpha activity account for reaction times (a proxy for predictions) on a trial-by-trial basis in an audiovisual delayed match-to-sample task which elicited predictions. Predictive ß feedback activated sensory representations in advance of predicted stimuli. Low-dose ketamine, an NMDAR blocker, but not the control drug dexmedetomidine, perturbed behavioral indices of predictions, their representation in higher-order cortex, feedback to posterior cortex, and pre-activation of sensory templates in higher-order sensory cortex. This study suggests that predictions depend on alpha activity in higher-order cortex, ß feedback, and NMDARs, and ketamine blocks access to learned predictive information.SIGNIFICANCE STATEMENT We learn the statistical regularities around us, creating associations between sensory stimuli. These associations can be exploited by generating predictions, which enable fast and efficient behavior. When predictions are perturbed, it can negatively influence perception and even contribute to psychiatric disorders, such as schizophrenia. Here we show that the frontal lobe generates predictions and sends them to posterior brain areas, to activate representations of predicted sensory stimuli before their appearance. Oscillations in neural activity (α and ß waves) are vital for these predictive mechanisms. The drug ketamine blocks predictions and the underlying mechanisms. This suggests that the generation of predictions in the frontal lobe, and the feedback pre-activating sensory representations in advance of stimuli, depend on NMDARs.

Depression and Anxiety Are Common Among Patients With Cirrhosis.

BACKGROUND & AIMS: Depression and anxiety can have negative effects on patients and are important to treat. There have been few studies of their prevalence among patients with cirrhosis. We aimed to characterize the prevalence and risk factors for depression and anxiety in a large multi-center cohort of patients with cirrhosis. METHODS: We conducted a telephone-based survey of patients with cirrhosis at 3 health systems in the United States (a tertiary-care referral center, a safety net system, and a Veterans hospital) from April through December 2018. Of 2871 patients approached, 1021 (35.6%) completed the survey. Depression and anxiety were assessed using the PHQ-9 (range 0-25) and STAI (range 20-80) instruments, with clinically significant values defined as PHQ-9 ≥15 and STAI ≥40. We performed multivariate logistic regression analysis to identify factors associated with significant depression and anxiety. RESULTS: The median PHQ-9 score was 7 (25th percentile-75th percentile, 3-12) and the median STAI score was 33 (25th percentile-75th percentile, 23-47); 15.6% of patients had moderately severe to severe depression and 42.6% of patients had high anxiety. In multivariable analyses, self-reported poor health (odds ratio [OR], 4.08; 95% CI, 1.79-9.28), being widowed (OR, 2.08; 95% CI, 1.07-4.05), fear of hepatocellular carcinoma (OR, 1.89; 95% CI, 1.04-3.42), higher household income (OR, 0.30; 95% CI, 0.10-0.95), and Hispanic ethnicity (OR, 0.57; 95% CI, 0.33-0.97) were associated with moderately severe to severe depression. Male sex (OR, 0.71; 95% CI, 0.51-0.98), self-reported poor health (OR, 2.73; 95% CI, 1.73-4.32), and fear of hepatocellular carcinoma (OR, 2.24; 95% CI, 1.33-3.78) were associated with high anxiety. CONCLUSIONS: Nearly 1 in 6 patients with cirrhosis have moderately severe to severe depression and nearly half have moderate-severe anxiety. Patients with cirrhosis should be evaluated for both of these disorders.

The effects of phylogeny, habitat and host characteristics on the thermal sensitivity of helminth development.

Helminth parasites are part of almost every ecosystem, with more than 300 000 species worldwide. Helminth infection dynamics are expected to be altered by climate change, but predicting future changes is difficult owing to lacking thermal sensitivity data for greater than 99.9% of helminth species. Here, we compiled the largest dataset to date on helminth temperature sensitivities and used the Metabolic Theory of Ecology to estimate activation energies (AEs) for parasite developmental rates. The median AE for 129 thermal performance curves was 0.67, similar to non-parasitic animals. Although exceptions existed, related species tended to have similar thermal sensitivities, suggesting some helminth taxa are inherently more affected by rising temperatures than others. Developmental rates were more temperature-sensitive for species from colder habitats than those from warmer habitats, and more temperature sensitive for species in terrestrial than aquatic habitats. AEs did not depend on whether helminth life stages were free-living or within hosts, whether the species infected plants or animals, or whether the species had an endotherm host in its life cycle. The phylogenetic conservatism of AE may facilitate predicting how temperature change affects the development of helminth species for which empirical data are lacking or difficult to obtain.

Loss of the aryl hydrocarbon receptor increases tumorigenesis in p53-deficient mice.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates cell fate via activation of a diverse set of genes. There are conflicting reports describing the role of AhR in cancer. AhR-knockout mice do not develop tumors spontaneously, yet the AhR can act as a tumor suppressor in certain contexts. Loss of tumor suppression by p53 is common in human cancer. To investigate AhR function in the absence of p53, we generated mice lacking both AhR and p53. Mice deficient for AhR and p53 had shortened lifespan, increased tumorigenesis, and an altered tumor spectrum relative to control mice lacking only p53. In addition, knockout of both AhR and p53 resulted in reduced embryonic survival and neonatal fitness. We also examined the consequences of loss of AhR in p53-heterozygous mice and observed a significantly reduced lifespan and enhanced tumor burden. These findings reveal an important role for the AhR as a tumor suppressor in the absence of p53 signaling and support the development of anti-cancer therapeutics that would promote the tumor suppressive actions of the AhR.

Routine Laboratory Tests are not Necessary After Primary Total Joint Arthroplasty: A Prospective Study Utilizing a Selective Algorithmic Approach.

BACKGROUND: Laboratory tests are obtained following total joint arthroplasty (TJA) despite a lack of supporting evidence. No prior study has prospectively analyzed the effect of discontinuing routine laboratory tests. This study aimed to determine whether discontinuing routine laboratory tests in TJA patients resulted in a difference in 90-day complications. METHODS: This was a prospective protocol change study at a high-volume center. Prior to protocol change, patients underwent routine laboratory tests following primary unilateral TJA (control group). After the change, an algorithmic approach was used to selectively order laboratory tests (protocol group). Patients with bleeding disorders, chronic obstructive pulmonary disease, arrhythmia, coronary artery disease, congestive heart failure, chronic renal failure, dementia, abnormal preoperative sodium, potassium, or hemoglobin <10 g/dL were excluded. In-hospital and 90-day data were collected. Student's t-test was used to analyze continuous variables and chi-squared test was used for categorical variables. A pre-hoc analysis examining the primary outcome required 607 patients per group to achieve 80% power. RESULTS: The protocol group included 937 patients, whereas the control group included 891 patients. The protocol group had fewer females and total hip arthroplasties. There were no differences in age, body mass index, American Society of Anesthesiologists classification, tranexamic acid administration, or estimated blood loss between the protocol and control groups. There were also no differences in transfusions, electrolyte corrections, unplanned consults, length of stay, or transfers. The protocol cohort had more fluid boluses and home discharges. There was no difference in 90-day complications between the 2 groups. CONCLUSIONS: This study utilizing an algorithmic approach to laboratory collection demonstrates that discontinuing routine laboratory tests following TJA is safe and effective. We believe this protocol can be implemented for most patients undergoing primary unilateral TJA.

Introduction of diabetic retinopathy screening into an antenatal clinic: Impact on maternal screening and diagnosis rates.

Pregnancy is a risk factor for the development and progression of diabetic retinopathy (DR) in women with pre-gestational diabetes. However, a minority of pregnant women with diabetes adhere to retinal screening recommendations. The introduction of an onsite retinal camera at our tertiary maternity hospital significantly increased the proportion of women who received at least one retinal screen during pregnancy (93.0% vs 54.3%, P < 0.001) and the identification of both DR and DR progression. We conclude that the use of a retinal camera in similar clinics is a feasible option to improve DR screening and diagnosis rates in pregnancy.

Patient-Reported Barriers Are Associated With Receipt of Hepatocellular Carcinoma Surveillance in a Multicenter Cohort of Patients With Cirrhosis.

BACKGROUND: More than 20% of patients with cirrhosis do not receive semi-annual hepatocellular carcinoma (HCC) surveillance as recommended. Few studies have evaluated the effects of patient-level factors on surveillance receipt. METHODS: We administered a telephone survey to a large cohort of patients with cirrhosis from 3 health systems (a tertiary care referral center, a safety-net health system, and Veterans Affairs) to characterize patient knowledge, attitudes, and perceived barriers of HCC surveillance. Multinomial logistic regression was performed to identify factors associated with HCC surveillance receipt (semi-annual and annual vs none) during the 12-month period preceding survey administration. RESULTS: Of 2871 patients approached, 1020 (35.5%) completed the survey. Patients had high levels of concern about developing HCC and high levels of knowledge about HCC. However, patients had knowledge deficits, including believing surveillance was unnecessary when physical examination and laboratory results were normal. Nearly half of patients reported barriers to surveillance, including costs (28.9%), difficulty scheduling (24.1%), and transportation (17.8%). In the year before the survey, 745 patients (73.1%) received 1 or more surveillance examination; 281 received on-schedule, semi-annual surveillance and 464 received annual surveillance. Semi-annual HCC surveillance (vs none) was significantly associated with receipt of hepatology subspecialty care (odds ratio, 30.1; 95% CI, 17.5-51.8) and inversely associated with patient-reported barriers (odds ratio, 0.62; 95% CI, 0.41-0.94). Patterns of associations comparing annual vs no surveillance were similar although the magnitude of effects were reduced. CONCLUSIONS: Patient-reported barriers such as knowledge deficits, costs, difficulty scheduling, and transportation are significantly associated with less frequent receipt of HCC surveillance, indicating a need for patient-centered interventions, such as patient navigation.

Molecular profiling reveals a hypoxia signature in breast implant-associated anaplastic large cell lymphoma.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently characterized T-cell malignancy that has raised significant patient safety concerns and led to worldwide impact on the implants used and clinical management of patients undergoing reconstructive or cosmetic breast surgery. Molecular signatures distinguishing BIA-ALCL from other ALCLs have not been fully elucidated and classification of BIA-ALCL as a WHO entity remains provisional. We performed RNA sequencing and gene set enrichment analysis comparing BIA-ALCLs to non-BIA-ALCLs and identified dramatic upregulation of hypoxia signaling genes including the hypoxia-associated biomarker CA9 (carbonic anyhydrase-9). Immunohistochemistry validated CA9 expression in all BIA-ALCLs, with only minimal expression in non-BIA-ALCLs. Growth induction in BIA-ALCL-derived cell lines cultured under hypoxic conditions was proportional to up-regulation of CA9 expression, and RNA sequencing demonstrated induction of the same gene signature observed in BIA-ALCL tissue samples compared to non-BIA-ALCLs. CA9 silencing blocked hypoxia-induced BIA-ALCL cell growth and cell cycle-associated gene expression, whereas CA9 overexpression in BIA-ALCL cells promoted growth in a xenograft mouse model. Furthermore, CA9 was secreted into BIA-ALCL cell line supernatants and was markedly elevated in human BIA-ALCL seroma samples. Finally, serum CA9 concentrations in mice bearing BIA-ALCL xenografts were significantly elevated compared to control serum. Together, these findings characterize BIA-ALCL as a hypoxia-associated neoplasm, likely attributable to the unique microenvironment in which it arises. These data support classification of BIA-ALCL as a distinct entity and uncover opportunities for investigating hypoxia-related proteins such as CA9 as novel biomarkers and therapeutic targets in this disease.

Empirical evidence that metabolic theory describes the temperature dependency of within-host parasite dynamics.

The complexity of host-parasite interactions makes it difficult to predict how host-parasite systems will respond to climate change. In particular, host and parasite traits such as survival and virulence may have distinct temperature dependencies that must be integrated into models of disease dynamics. Using experimental data from Daphnia magna and a microsporidian parasite, we fitted a mechanistic model of the within-host parasite population dynamics. Model parameters comprising host aging and mortality, as well as parasite growth, virulence, and equilibrium abundance, were specified by relationships arising from the metabolic theory of ecology. The model effectively predicts host survival, parasite growth, and the cost of infection across temperature while using less than half the parameters compared to modeling temperatures discretely. Our results serve as a proof of concept that linking simple metabolic models with a mechanistic host-parasite framework can be used to predict temperature responses of parasite population dynamics at the within-host level.

Revisiting nocturnal heart rate and heart rate variability in insomnia: A polysomnography-based comparison of young self-reported good and poor sleepers.

Primary insomnia is often considered a disorder of 24-hr hyperarousal. Numerous attempts have been made to investigate nocturnal heart rate (HR) and its variability (HRV) as potential pathophysiological hallmarks of altered arousal levels in insomnia, with mixed results. We have aimed to overcome some of the pitfalls of previous studies by using a young, medication-free, age- and gender-matched population consisting of 43 students aged 18-30 years half with a subthreshold insomnia complaint. We employed at-home ambulatory polysomnography and compared this attenuated insomnia group to a good sleeping group. The poor sleepers had significantly higher wake after sleep onset, arousal count, mean HR in all sleep stages (with the exception of Stage 1) and lower sleep efficiency. Consistent with previous research, we also found a significant group-by-sleep stage interaction in the prediction of nocturnal HR, highlighting the insomnia group to have a lower wake-sleep HR reduction compared to good sleepers. When restricting our analyses to insomnia with objectively determined short sleep duration, we found significantly lower standard deviation of RR intervals (SDNN; a measure of HRV) compared to good sleepers. Taken together, this lends credence to the hyperarousal model of insomnia and may at least partially explain the increased prevalence of cardiovascular morbidity and mortality observed in patients with insomnia.

Epigenetic regulation of the ITGB4 gene in prostate cancer.

BACKGROUND: Examination of epigenetic changes at the ITGB4 gene promoter reveals altered methylation at different stages of prostate tumour progression and these changes may, in part, explain the complex patterns of gene expression of this integrin observed. Transcriptional re-programming perturbs expression of cell adhesion molecules and underpins metastatic tumour cell behaviour. Decreasing expression of the cell adhesion molecule ITGB4, which encodes the beta subunit of the integrin, alpha6 beta4 (α6ß4), has been correlated with increased tumour aggressiveness and metastasis in multiple tumour types including prostate cancer. Paradoxically, in vitro studies in tumour cell models demonstrate that ITGB4 mediates cell mobility and invasion. Herein we examined whether transcriptional re-programming by methylation influenced ITGB4 gene expression at different stages of prostate cancer progression. Bisulphite sequencing of a large CpG island in the ITGB4 gene promoter identified differentially methylated regions in prostate cancer cell lines representing a localised tumour (22Rv1), lymph node metastasis (LNCaP), and a bone metastasis (PC-3). The highest levels of methylation were observed in the CpG island surrounding the ITGB4 transcription start site in PC-3 cells, and this observation also correlated with higher gene expression of ITGB4 in these cells. Furthermore, PC-3 cells expressed two distinct transcripts, using an alternate transcription start site, which was not detected in other cell lines. In prostate tumour biopsy samples, patterns of methylation across the ITGB4 promoter were similar overall in matched primary and metastatic samples (n = 4 pairs), with a trend toward loss of methylation at specific sites in metastatic lesions.

Lynch syndrome associated endometrial carcinomas in Western Australia: an analysis of universal screening by mismatch repair protein immunohistochemistry.

BACKGROUND: In 2016 universal screening with mismatch repair protein immunohistochemistry in all newly diagnosed endometrial carcinomas was introduced in Western Australia. OBJECTIVE: To compare the prevalence of Lynch syndrome associated endometrial carcinomas between 2016 and 2019 with a historical control (2015). Additionally, to compare the number of cases appropriately referred for genetic assessment. METHODS: A cross-sectional study of cases presented at the Western Australia gynecologic oncology tumor board was carried out. The primary outcome was the prevalence of Lynch syndrome associated endometrial carcinomas. A secondary outcome was the number of cases appropriately referred for genetic assessment. The following variables were extracted: date of birth; age at diagnosis; vital status; tumor mismatch repair protein expression status (retained or lost) and if lost, the specific mismatch repair protein deficiency; patients who were referred to a genetic clinic; and family history, if recorded. Data were collected from the clinical databases of the Familial Cancer Program at Genetic Services of Western Australia and WOMEN Center, to determine whether patients were appropriately referred for genetic evaluation and to ascertain the results of genetic testing. RESULTS: Between 2016 and 2019, there were 1040 new endometrial carcinomas. Tumors of 883 (85%) patients underwent mismatch repair protein immunohistochemistry compared with 117 of 199 patients (59%) in 2015 (χ2 73.14, p<0.001). Of 883 tumors tested, 242 (27%) showed loss of mismatch repair protein expression. In 2015, 30 (26%) tumors of 117 tested showed loss of mismatch repair protein expression. During the 4 years of universal screening, 13 (1.5%) of 883 patients screened were diagnosed with Lynch syndrome compared with 2 (1.7%) of 117 in 2015 (Fisher's exact test 0.04, p=0.69). In 2015, 11 (37%) of 30 patients with loss of mismatch repair protein expression were not referred for genetic assessment compared with 36 (17%) of 209 patients in the universal screening group (χ2 6.28, p=0.02). No cases of Lynch syndrome were diagnosed in patients aged over 70 years. CONCLUSIONS: Universal immunohistochemical screening did not increase the proportion of Lynch syndrome associated endometrial carcinomas identified, although the study was underpowered to detect small differences. There was an improvement in appropriate referrals for genetic assessment.

Topographic organization of connections between prefrontal cortex and mediodorsal thalamus: Evidence for a general principle of indirect thalamic pathways between directly connected cortical areas.

Our ability to act flexibly, according to goals and context, is known as cognitive control. Hierarchical levels of control, reflecting different levels of abstraction, are represented across prefrontal cortex (PFC). Although the mediodorsal thalamic nucleus (MD) is extensively interconnected with PFC, the role of MD in cognitive control is unclear. Tract tracer studies in macaques, involving subsets of PFC areas, have converged on coarse MD-PFC connectivity principles; but proposed finer-grained topographic schemes, which constrain interactions between MD and PFC, disagree in many respects. To investigate a unifying topographic scheme, we performed probabilistic tractography on diffusion MRI data from eight macaque monkeys, and estimated the probable paths connecting MD with each of all 19 architectonic areas of PFC. We found a connectional topography where the orderly progression from ventromedial to anterior to posterolateral PFC was represented from anteromedial to posterolateral MD. The projection zones of posterolateral PFC areas in MD showed substantial overlap, and those of ventral and anteromedial PFC areas in MD overlapped. The exception was cingulate area 24: its projection zone overlapped with projections zones of all other PFC areas. Overall, our data suggest that nearby, functionally related, directly connected PFC areas have partially overlapping projection zones in MD, consistent with a role for MD in coordinating communication across PFC. Indeed, the organizing principle for PFC projection zones in MD appears to reflect the flow of information across the hierarchical, multi-level PFC architecture. In addition, cingulate area 24 may have privileged access to influence thalamocortical interactions involving all other PFC areas.

HEART Score Risk Stratification of Low-Risk Chest Pain Patients in the Emergency Department: A Systematic Review and Meta-Analysis.

STUDY OBJECTIVE: The objectives of this systematic review and meta-analysis are to appraise the evidence in regard to the diagnostic accuracy of a low-risk History, ECG, Age, Risk Factors, and Troponin (HEART) score for prediction of major adverse cardiac events in emergency department (ED) patients. These included 4 subgroup analyses: by geographic region, the use of a modified low-risk HEART score (traditional HEART score [0 to 3] in addition to negative troponin results), using conventional versus high-sensitivity troponin assays in the HEART score, and a comparison of different post-ED-discharge patient follow-up intervals. METHODS: We searched MEDLINE, EBSCO, Web of Science, and Cochrane Database for studies on the diagnostic performance of low-risk HEART scores to predict major adverse cardiac events among ED chest pain patients. Two reviewers independently screened articles for inclusion, assessed the quality of studies with both an adapted Quality Assessment of Diagnostic Accuracy Studies version 2 tool and an internally developed tool that combined components of the Quality in Prognostic Studies; Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies; and Grading of Recommendations Assessment, Development and Evaluation. Pooled sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratios were calculated. RESULTS: There were 25 studies published from 2010 to 2017, with a total of 25,266 patients included in the final meta-analysis, of whom 9,919 (39.3%) were deemed to have low-risk HEART scores (0 to 3). Among patients with low-risk HEART scores, short-term major adverse cardiac events (30 days to 6 weeks) occurred in 2.1% of the population (182/8,832) compared with 21.9% of patients (3,290/15,038) with non-low-risk HEART scores (4 to 10). For patients with HEART scores of 0 to 3, the pooled sensitivity of short-term major adverse cardiac event predictions was 0.96 (95% confidence interval [CI] 0.93 to 0.98), specificity was 0.42 (95% CI 0.36 to 0.49), positive predictive value was 0.19 (95% CI 0.14 to 0.24), negative predictive value was 0.99 (95% CI 0.98 to 0.99), positive likelihood ratio was 1.66 (95% CI 1.50 to 1.85), and negative likelihood ratio was 0.09 (95% CI 0.06 to 0.15). Subgroup analysis showed that lower short-term major adverse cardiac events occurred among North American patients (0.7%), occurred when modified low-risk HEART score was used (0.8%), or occurred when high-sensitivity troponin was used for low-risk HEART score calculations (0.8%). CONCLUSION: In this meta-analysis, despite its use in different patient populations, the troponin type used, and timeline of follow-up, a low-risk HEART score had high sensitivity, negative predictive value, and negative likelihood ratio for predicting short-term major adverse cardiac events, although risk of bias and statistical heterogeneity were high.