Background Previous studies regarding survival in patients with splanchnic vein thrombosis (SVT) are limited. This study measured overall survival in a large cohort of SVTs through linkage to ...population-based data. Methods and Results Using a previously derived text-search algorithm, we screened the reports of all abdominal ultrasound and contrast-enhanced computed tomography studies at The Ottawa Hospital over 14 years. Screen-positive reports were manually reviewed by at least 2 authors to identify definite SVT cases by consensus. Images of uncertain studies were independently reviewed by 2 radiologists. One thousand five hundred sixty-one adults with SVT (annual incidence ranging from 2.8 to 5.9 cases/10 000 patients) were linked with population-based data sets to measure the presence of concomitant cancer and survival status. Thrombosis involved multiple veins in 314 patients (20.1%), most commonly the portal vein (n=1410, 90.3%). Compared with an age-sex-year matched population, patients with SVT had significantly reduced survival in particular with local cancer (adjusted relative excess risk for recent cases 12.0 95% CI, 9.8-14.6 and for remote cases 9.7 7.7-12.2), distant cancer (relative excess risk for recent cases 5.7 4.5-7.3 and for remote cases 5.4 4.4-6.6), cirrhosis (relative excess risk 8.2 5.3-12.7), and previous venous thromboembolism (relative excess risk 3.8 2.4-6.0). One hundred fifty (23.9%) of patients >65 years of age were anticoagulated within 1 month of diagnosis. Conclusions SVT is more common than expected. Most patients have cancer and the portal vein is by far the most common vein involved. Compared with the general population, patients with SVT had significantly reduced survival, particularly in patients with concomitant cancer, cirrhosis, and previous venous thromboembolic disease. Most elderly patients did not receive anticoagulant therapy.
Diabetic Neuropathies Elafros, Melissa A; Callaghan, Brian C
Continuum (Minneapolis, Minn.),
10/2023, Volume:
29, Issue:
5
Journal Article
This article provides an up-to-date review of the diagnosis and management of the most common neuropathies that occur in patients with diabetes.
The prevalence of diabetes continues to grow worldwide ...and, as a result, the burden of diabetic neuropathies is also increasing. Most diabetic neuropathies are caused by hyperglycemic effects on small and large fiber nerves, and glycemic control in individuals with type 1 diabetes reduces neuropathy prevalence. However, among people with type 2 diabetes, additional factors, particularly metabolic syndrome components, play a role and should be addressed. Although length-dependent distal symmetric polyneuropathy is the most common form of neuropathy, autonomic syndromes, particularly cardiovascular autonomic neuropathy, are associated with increased mortality, whereas lumbosacral radiculoplexus neuropathy and treatment-induced neuropathy cause substantial morbidity. Recent evidence-based guidelines have updated the recommended treatment options to manage pain associated with distal symmetric polyneuropathy of diabetes.
Identifying and appropriately diagnosing the neuropathies of diabetes is key to preventing progression. Until better disease-modifying therapies are identified, management remains focused on diabetes and metabolic risk factor control and pain management.
Our present knowledge of the regulation of mammalian endothelial cell differentiation has been largely derived from studies of mouse embryonic development. However, unique mechanisms and hierarchy of ...signals that govern human endothelial cell development are unknown and, thus, explored in these studies.
Using human embryonic stem cells as a model system, we were able to reproducibly and robustly generate differentiated endothelial cells via coculture on OP9 marrow stromal cells. We found that, in contrast to studies in the mouse, bFGF and VEGF had no specific effects on the initiation of human vasculogenesis. However, exogenous Ihh promoted endothelial cell differentiation, as evidenced by increased production of cells with cobblestone morphology that coexpress multiple endothelial-specific genes and proteins, form lumens, and exhibit DiI-AcLDL uptake. Inhibition of BMP signaling using Noggin or BMP4, specifically, using neutralizing antibodies suppressed endothelial cell formation; whereas, addition of rhBMP4 to cells treated with the hedgehog inhibitor cyclopamine rescued endothelial cell development.
Our studies revealed that Ihh promoted human endothelial cell differentiation from pluripotent hES cells via BMP signaling, providing novel insights applicable to modulating human endothelial cell formation and vascular regeneration for human clinical therapies.
From 2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) household transmission studies (enrolling April 2020 to January 2022) with rapid enrollment and specimen collection for 14 days, ...61% (43/70) of primary cases had culturable virus detected ≥6 days post-onset. Risk of secondary infection among household contacts tended to be greater when primary cases had culturable virus detected after onset. Regardless of duration of culturable virus, most secondary infections (70%, 28/40) had serial intervals <6 days, suggesting early transmission. These data examine viral culture as a proxy for infectiousness, reaffirm the need for rapid control measures after infection, and highlight the potential for prolonged infectiousness (≥6 days) in many individuals.
•Little is known about how parents and adolescents affect each other’s stress-related physiology, such as their diurnal rhythm of cortisol.•In this study, we found that adolescent cortisol patterns ...predicted their parents’ cortisol patterns the next day.•However, parents’ cortisol did not predict their adolescents’ cortisol patterns the next day.•The models support a primarily child-driven process of stress transmission in families.
Prior studies suggest bidirectional relationships between parent and adolescent behavior. This study examined how parents and their adolescent child’s cortisol patterns are associated across days and if there are bidirectional associations between parent and child cortisol. Participants included two samples of employees and their children who participated in a daily diary study where diurnal salivary cortisol was collected on four study days (N = 318 dyads, Myouth age = 13.18 years, 52 % female). Autoregressive cross-lagged models were used to estimate parent-driven effects (parent cortisol effects on adolescent cortisol) and adolescent-driven effects (adolescent cortisol effects on parent cortisol). Adolescents’ steeper cortisol awakening response (CAR) was significantly associated with parents’ steeper CAR the following day. Adolescents’ higher bedtime cortisol levels were also significantly associated with parents’ higher bedtime cortisol levels the following day. Parents’ cortisol did not predict their children’s next-day cortisol. Results support a primarily adolescent-driven process of stress transmission in families. These results suggest that interventions to reduce adolescent stress, as well as to reduce parents’ reactivity to adolescents, may be warranted.
In current care, patients' personal and self-reported family histories are primarily used to determine whether genetic testing for hereditary endocrine tumor syndromes (ETS) is indicated. Population ...genomic screening for other conditions has increased ascertainment of individuals with pathogenic/likely pathogenic (P/LP) variants, leading to improved management and earlier diagnoses. It is unknown whether such benefits occur when screening broader populations for P/LP ETS variants. This manuscript assesses clinical utility outcomes of a large, unselected, healthcare-based genomic screening program by describing personal and family history of syndrome-related features, risk management behaviors after result disclosure, and rates of relevant post-disclosure diagnoses in patient-participants with P/LP ETS variants.
Observational study of individuals informed of a P/LP variant in MEN1, RET, SDHAF2, SDHB, SDHC, SDHD, or VHL through Geisinger's MyCode Community Health Initiative between June 2016 and October 2019. Electronic health records (EHRs) of participants were evaluated for a report of pre-disclosure personal and self-reported family histories and post-disclosure risk management and diagnoses.
P/LP variants in genes of interest were identified in 199 of 130,490 (1 in 656) adult Geisinger MyCode patient-participants, 80 of which were disclosed during the study period. Eighty-one percent (n = 65) did not have prior evidence of the result in their EHR and, because they were identified via MyCode, were included in further analyses. Five participants identified via MyCode (8%) had a personal history of syndrome-related features; 16 (25%) had a positive self-reported family history. Time from result disclosure to EHR review was a median of 0.7 years. Post-disclosure, 36 (55.4%) completed a recommended risk management behavior; 11 (17%) were diagnosed with a syndrome-related neoplasm after completing a risk management intervention.
Broader screening for pathogenic/likely pathogenic variants associated with endocrine tumor syndromes enables detection of at-risk individuals, leads to the uptake of risk management, and facilitates relevant diagnoses. Further research will be necessary to continue to determine the clinical utility of screening diverse, unselected populations for such variants.
Oral breast cancer prevention medications entail systemic exposure, limiting acceptance by high‐risk women. Delivery through the breast skin, although an attractive alternative, requires ...demonstration of drug distribution throughout the breast. We conducted a randomized double‐blind, placebo‐controlled phase II clinical trial comparing telapristone acetate, a progesterone receptor antagonist, administered orally (12 mg/day) or transdermally (12 mg/breast) for 4 ± 1 weeks to women planning mastectomy. Plasma and tissue concentrations, measured at five locations in the mastectomy specimen using liquid chromatography tandem mass spectrometry were compared. In 60 evaluable subjects, median drug concentration (ng/g tissue) was 103 (interquartile range (IQR): 46.3–336) in the oral vs. 2.82 (IQR: 1.4–5.5) in the transdermal group. Despite poor dermal permeation, within‐breast drug distribution pattern was identical in both groups (R2 = 0.88, P = 0.006), demonstrating that transdermally and orally delivered drug is distributed similarly through the breast, and is strongly influenced by tissue adiposity (P < 0.0001). Other skin‐penetrant drugs should be tested for breast cancer prevention.
Background
Perceived risks of hyperkalemia and acute renal insufficiency may limit use of mineralocorticoid receptor antagonist (MRA) therapy in patients with heart failure, especially those with ...diabetes mellitus or chronic kidney disease.
Methods and Results
Using clinical registry data linked to Medicare claims, we analyzed patients hospitalized with heart failure between 2005 and 2013 with a history of diabetes mellitus or chronic kidney disease. We stratified patients by MRA use at discharge. We used inverse probability–weighted proportional hazards models to assess associations between MRA therapy and 30‐day, 1‐year, and 3‐year mortality, all‐cause readmission, and readmission for heart failure, hyperkalemia, and acute renal insufficiency. We performed interaction analyses for differential effects on 3‐year outcomes for reduced, borderline, and preserved ejection fraction. Of 16 848 patients, 12.3% received MRA therapy at discharge. Higher serum creatinine was associated with lower odds of MRA use (odds ratio, 0.66; 95% confidence interval, 0.61–0.71); serum potassium was not (odds ratio, 1.00; 95% confidence interval, 0.90–1.11). There was no mortality difference between groups. MRA therapy was associated with greater risks of readmission for hyperkalemia and acute renal insufficiency and lower risks of long‐term all‐cause readmission. Patients on MRA therapy with borderline or preserved ejection fraction had greater risks of readmission for hyperkalemia (P=0.02) and acute renal insufficiency (P<0.001); patients with reduced ejection fraction did not.
Conclusions
Among patients with heart failure and diabetes mellitus or chronic kidney disease, MRA use was associated with lower risk of all‐cause readmission despite greater risk of hyperkalemia and acute renal insufficiency.
Malignant hyperthermia (MH) susceptibility is a heritable musculoskeletal disorder that can present as a potentially fatal hypermetabolic response to triggering anesthesia agents. Genomic screening ...for variants in MH-associated genes RYR1 and CACNA1S provides an opportunity to prevent morbidity and mortality. There are limited outcomes data from disclosing variants in RYR1, the most common MH susceptibility gene, in unselected populations. The authors sought to identify the rate of MH features or fulminant episodes after triggering agent exposure in an unselected population undergoing genomic screening including actionable RYR1 variants.
The MyCode Community Health Initiative by Geisinger (USA) is an electronic health record-linked biobank that discloses pathogenic and likely pathogenic variants in clinically actionable genes to patient-participants. Available electronic anesthesia and ambulatory records for participants with actionable RYR1 results returned through December 2020 were evaluated for pertinent findings via double-coded chart reviews and reconciliation. Descriptive statistics for observed phenotypes were calculated.
One hundred fifty-two participants had an actionable RYR1 variant disclosed during the study period. None had previous documented genetic testing for MH susceptibility; one had previous contracture testing diagnosing MH susceptibility. Sixty-eight participants (44.7%) had anesthesia records documenting triggering agent exposure during at least one procedure. None received dantrolene treatment or had documented muscle rigidity, myoglobinuria, hyperkalemia, elevated creatine kinase, severe myalgia, or tea-colored urine. Of 120 possibly MH-related findings (postoperative intensive care unit admissions, hyperthermia, arterial blood gas evaluation, hypercapnia, or tachycardia), 112 (93.3%) were deemed unlikely to be MH events; 8 (6.7%) had insufficient records to determine etiology.
Results demonstrate a low frequency of classic intraanesthetic hypermetabolic phenotypes in an unselected population with actionable RYR1 variants. Further research on the actionability of screening for MH susceptibility in unselected populations, including economic impact, predictors of MH episodes, and expanded clinical phenotypes, is necessary.
Abstract
Background
SARS-CoV-2 variants of concern, such as Omicron (B.1.1.529), continue to emerge. Assessing the impact of their potential viral properties on the probability of future transmission ...dominance and public health burden is fundamental in guiding ongoing COVID-19 control strategies.
Methods
With an individual-based transmission model, OpenCOVID, we simulated three viral properties; infectivity, severity, and immune-evading ability, all relative to the Delta variant, to identify thresholds for Omicron’s or any emerging VOC’s potential future dominance, impact on public health, and risk to health systems. We further identify for which combinations of viral properties current interventions would be sufficient to control transmission.
Results
We show that, with first-generation SARS-CoV-2 vaccines and limited physical distancing in place, a VOC’s potential future dominance is primarily driven by its infectivity, which does not always lead to an increased public health burden. However, we also show that highly immune-evading variants that become dominant, even in the case of reduced variant severity, would likely require alternative measures to avoid strain on health systems, such as strengthened physical distancing measures, novel treatments, and second-generation vaccines. Expanded vaccination, that includes a booster dose for adults and child vaccination strategies, is projected to have the biggest public health benefit for a highly infective, highly severe VOC with low immune-evading capacity.
Conclusions
These findings provide quantitative guidance to decision-makers at a critical time while Omicron’s properties are being assessed and preparedness for emerging VOCs is eminent. We emphasise the importance of both genomic and population epidemiological surveillance.
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