Isokinetic Shoulder Strength and its Associations to Injury in Tactical Populations: A Critical Review.

The aim of this review is to evaluate existing isokinetic testing protocols for the shoulder in tactical occupations, document their shoulder strength profiles, and determine any associations to shoulder injury. Four electronic databases were searched (Medline/Pubmed, Ovid/Emcare, CINAHL/Ebsco and Embase) using the keywords police OR law enforcement, firefighter, military, AND isokinetic. Articles were eligible if they had at least one cohort of a tactical population and included isokinetic testing of the glenohumeral joint. The search yielded 275 articles. After screening for duplicates and inclusion criteria, 19 articles remained for review, six of which assessed injury correlation. 17 articles evaluated military personnel and two examined firefighters. Articles were categorized by study design, population, isokinetic protocols, strength outcome measures and statistical measures. Concentric internal rotation (IR) and external rotation (ER) strength at 60 degrees/second were reported most frequently (84% of cases). There was a paucity of testing speeds, repetition ranges and contraction types evaluated when compared to existing literature in other populations with high shoulder injury occurrence such as overhead and collision athletes. Outside of military cohorts, there is limited data available to characterise the isokinetic strength profile of the shoulder in tactical occupations. Meta-analysis for injury association was unable to be performed due to independent variable and statistical heterogeneity. However, a best evidence synthesis suggested conflicting evidence to support the association of injury with isokinetic strength testing in tactical populations. Future studies should prioritise prospective designs utilising variable speeds, repetition schemes and contraction types to better capture the dynamic occupational demands in tactical groups.

Unique features of dyslipidemia in women across a lifetime and a tailored approach to management.

Purpose of Review: Cardiovascular disease is a leading cause of death worldwide. Dyslipidemia is a critical modifiable risk factor for the prevention of cardiovascular disease. Dyslipidemia affects a large population of women and is especially pervasive within racial/ethnic minorities. Recent Findings: Dyslipidemia in pregnancy leads to worse outcomes for patients and creates increased cardiovascular risk for women at an older age. However, women remain underscreened and undertreated compared to men. Females also comprise a small portion of clinical trial participants for lipid lowering agents with increased disease prevalence compared to trial representation. However, recent lipid trials have shown different efficacies of therapies such as ezetimibe, inclisiran, and bempedoic acid with a greater relative benefit for women. Summary: Pathophysiology of dyslipidemia varies between men and women and across a woman's lifetime. While increased lipid levels or lipid imbalances are more common in postmenopausal women over age 50, conditions such as PCOS and FH produce higher cardiovascular risk for young women.Best practices for management of women with dyslipidemia include early screening with lifestyle intervention and pharmacotherapy with statin and non-statin agents to achieve guideline directed LDL-C thresholds.

A focused update to the 2019 NLA scientific statement on use of lipoprotein(a) in clinical practice.

Since the 2019 National Lipid Association (NLA) Scientific Statement on Use of Lipoprotein(a) in Clinical Practice was issued, accumulating epidemiological data have clarified the relationship between lipoprotein(a) [Lp(a)] level and cardiovascular disease risk and risk reduction. Therefore, the NLA developed this focused update to guide clinicians in applying this emerging evidence in clinical practice. We now have sufficient evidence to support the recommendation to measure Lp(a) levels at least once in every adult for risk stratification. Individuals with Lp(a) levels <75 nmol/L (30 mg/dL) are considered low risk, individuals with Lp(a) levels ≥125 nmol/L (50 mg/dL) are considered high risk, and individuals with Lp(a) levels between 75 and 125 nmol/L (30-50 mg/dL) are at intermediate risk. Cascade screening of first-degree relatives of patients with elevated Lp(a) can identify additional individuals at risk who require intervention. Patients with elevated Lp(a) should receive early, more-intensive risk factor management, including lifestyle modification and lipid-lowering drug therapy in high-risk individuals, primarily to reduce low-density lipoprotein cholesterol (LDL-C) levels. The U.S. Food and Drug Administration approved an indication for lipoprotein apheresis (which reduces both Lp(a) and LDL-C) in high-risk patients with familial hypercholesterolemia and documented coronary or peripheral artery disease whose Lp(a) level remains ≥60 mg/dL [∼150 nmol/L)] and LDL-C ≥ 100 mg/dL on maximally tolerated lipid-lowering therapy. Although Lp(a) is an established independent causal risk factor for cardiovascular disease, and despite the high prevalence of Lp(a) elevation (∼1 of 5 individuals), measurement rates are low, warranting improved screening strategies for cardiovascular disease prevention.

Harnessing RNA Interference for Cholesterol Lowering: The Bench-to-Bedside Story of Inclisiran.

Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone of reducing risk for atherosclerotic cardiovascular disease. Despite the approval of nonstatin therapies for LDL-C lowering over the past 2 decades, these medications are underused, and most patients are still not at guideline-recommended LDL-C goals. Barriers include poor adherence, clinical inertia, concern for side effects, cost, and complex prior authorization processes. With atherosclerotic cardiovascular disease-related mortality increasing globally, there remains a need for additional therapeutic options for lowering LDL-C as part of an atherosclerotic cardiovascular disease prevention strategy. Following the identification of PCSK9 (proprotein convertase subtilisin/kexin type 9) as a promising therapeutic target, inclisiran was developed using the natural process of RNA interference for robust, sustained prevention of hepatic PCSK9 synthesis. Twice-yearly maintenance subcutaneous inclisiran (following initial loading doses at Day 1 and Day 90) reduces circulating LDL-C levels by ≈50% versus placebo when added to maximally tolerated statins. Long-term safety and tolerability of inclisiran have been assessed, with studies underway to evaluate the effects of inclisiran on cardiovascular outcomes and to provide additional safety and effectiveness data. In 2021, <20 years after the discovery of PCSK9, inclisiran became the first RNA interference therapeutic approved in the United States for LDL-C lowering in patients with established atherosclerotic cardiovascular disease or familial hypercholesterolemia and has since been approved for use in patients with primary hyperlipidemia. This article reviews the journey of inclisiran from bench to bedside, including early development, the clinical trial program, key characteristics of inclisiran, and practical points for its use in the clinic.

Stripe noise removal in conductive atomic force microscopy.

Conductive atomic force microscopy (c-AFM) can provide simultaneous maps of the topography and electrical current flow through materials with high spatial resolution and it is playing an increasingly important role in the characterization of novel materials that are being investigated for novel memory devices. However, noise in the form of stripe features often appear in c-AFM images, challenging the quantitative analysis of conduction or topographical information. To remove stripe noise without losing interesting information, as many as sixteen destriping methods are investigated in this paper, including three additional models that we propose based on the stripes characteristics, and thirteen state-of-the-art destriping methods. We have also designed a gradient stripe noise model and obtained a ground truth dataset consisting of 800 images, generated by rotating and cropping a clean image, and created a noisy image dataset by adding random intensities of simulated noise to the ground truth dataset. In addition to comparing the results of the stripe noise removal visually, we performed a quantitative image quality comparison using simulated datasets and 100 images with very different strengths of simulated noise. All results show that the Low-Rank Recovery method has the best performance and robustness for removing gradient stripe noise without losing useful information. Furthermore, a detailed performance comparison of Polynomial fitting and Low-Rank Recovery at different levels of real noise is presented.

A Fast Alpha-Tree Algorithm for Extreme Dynamic Range Pixel Dissimilarities.

The α-tree algorithm is a useful hierarchical representation technique which facilitates comprehension of images such as remote sensing and medical images. Most α-tree algorithms make use of priority queues to process image edges in a correct order, but because traditional priority queues are inefficient in α-tree algorithms using extreme-dynamic-range pixel dissimilarities, they run slower compared with other related algorithms such as component tree. In this paper, we propose a novel hierarchical heap priority queue algorithm that can process α-tree edges much more efficiently than other state-of-the-art priority queues. Experimental results using 48-bit Sentinel-2 A remotely sensed images and randomly generated images have shown that the proposed hierarchical heap priority queue improved the timings of the flooding α-tree algorithm by replacing the heap priority queue with the proposed queue: 1.68 times in 4-N and 2.41 times in 8-N on Sentinel-2 A images, and 2.56 times and 4.43 times on randomly generated images.

Laparoscopic prepregnancy transabdominal cerclage: operative and pregnancy outcomes for a novel technique of suture placement using port closure device.

Transabdominal cerclage is an effective surgical intervention for preterm birth prevention. Placement of cervical sutures using a port closure device for prepregnancy laparoscopic abdominal cerclage has been used at our unit in recent years. We report the operative and pregnancy outcomes for prepregnancy laparoscopic abdominal cerclage using the port closure device and compare it with the outcomes of the traditional approach. For prepregnancy laparoscopic transabdominal cerclage (n=52), the port closure device approach was associated with less blood loss during surgery (0.95±4.4 mL vs 5.4±15.7 mL; P=.007) and a shorter hospital length of stay (0.0; 0.0-0.0 days vs 1.0; 0.0-1.0 days; P<.001). There were also trends toward shorter operating times (41.4±15.3 minutes vs 50.1±18.0 minutes; P=.167) and lower perioperative complication rates (0.0%; 0/21 vs 16.1%; 5/31; P=.065) when compared with the traditional technique. There was no significant difference between the port closure device technique and the traditional approach in the rate of preterm birth in a subsequent pregnancy (0.0%; 0/9 vs 22.6%; 7/39; P=.248). Use of the port closure device for suture placement during prepregnancy laparoscopic cerclage for preterm birth prevention was reported. This technique was associated with less blood loss and a shorter hospital length of stay, had trends toward shorter operating times and lower perioperative complication rates, and had similar rates of preterm birth.

Cognition and psychological wellbeing in hypopituitary patients.

Hypopituitarism (HP) frequently occurs in patients presenting with sellar masses and despite recent advances in therapeutic options, HP patients consistently suffer from impaired quality of life due to psychological distress and cognitive dysfunction. These neurocognitive complications tend to persist in spite of surgical or biochemical remission of the disease making it especially challenging to segregate the effect of HP per se from other comorbidities such as the effect of tumour, surgery, radiation therapy, or complications caused by excess hormone production. Regardless, there is ample evidence to suggest that receptors for various pituitary hormones are abundantly expressed in key areas of central nervous system that are associated with memory and behaviour function and HP is also associated with poor sleep which can further exacerbate neurocognitive dysfunction. There is also evidence that hormonal replacement in HP patients partially restores these neurocognitive functions and improves sleep disorders. However, there is a need for creating better awareness among healthcare providers interacting with HP patients to enhance an earlier recognition of these disorder and their impact on quality of life despite initial remission. Importantly, there is a need to not only develop better and more cost-effective replacement therapies that would closely mimic the physiological hormonal release patterns, but also develop coping strategies for HP patients suffering from these complications.

Spinal cord stimulation for visceral pain associated with medullary sponge kidney.

Chronic pain is a common reason for which people in the USA seek medical care. It is linked to opioid consumption, anxiety and a reduction in quality of life. Over the past 50 years, spinal cord stimulation (SCS) has evolved as a safe and efficacious treatment for chronic pain etiologies. The authors present the first known case of SCS for pain due to medullary sponge kidney disease. This report adds to the growing body of literature supporting the use of SCS for treating visceral organ pain, while also highlighting the utility of ventral lead placement for treating visceral pain. As SCS utilization increases, it is expected that there will be a decrease in opioid consumption, and this will help us contain the opioid epidemic.

Chronic pain is one of the most common reasons that people in the USA seek medical care. It is associated with an increased reliance on opioids, anxiety, depression and a lower quality of life. Over the past 50 years, a treatment modality known as spinal cord stimulation (SCS) has emerged and evolved. Based on evidence, SCS has shown promising results in treating chronic pain related to different causes and has also led to an improvement in the quality of life in those suffering from pain. In this case report, the authors present a case of a patient with chronic pain due to recurrent kidney stones secondary to their hereditary kidney disease, and who responded well to treatment with SCS. The patient self-reported almost 80% pain relief after undergoing treatment with SCS as well as an improved quality of life, based on their ability to engage in their daily professional and leisurely activities without being so restricted by pain from their recurrent kidney stones. This case report adds to the growing body of literature that underscores the utility of SCS in treating a variety of pain mediated pathologies. As SCS continues to show promising results, we hope that SCS usage to target pain will increase, and this will lead to a decrease in opioid prescriptions and help curb the opioid epidemic.

Time-Restricted Eating: A Novel Dietary Strategy for Cardiac Rehabilitation.

Cardiac rehabilitation (CR) is a multimodal program considered to be the standard of care for secondary prevention of cardiovascular disease (CVD). The primary goals of CR are managing CVD risk factors and improving quality of life. Exercise is the cornerstone, but nutrition education delivered by registered dietitians (RDs) is a core component of CR. Yet patient constraints to adherence to dietary change and limited availability of RDs represent major barriers to the success of completion of nutrition intervention during CR. Therefore, nutritional strategies that reduce CVD risk factors, barriers to adherence, and have capacity for broad dissemination are warranted within CR programs. In this review, we propose time-restricted eating (TRE) as a nutrition strategy to improve the outcomes of CR by drawing on parallels to CVD in other populations and describe the available preliminary data on the efficacy of TRE for CVD. TRE is a dietary strategy that involves alternating periods of fasting and consumption of calories each day. We outline the feasibility, safety, and beneficial cardiometabolic impact of TRE from TRE research in other populations. We also discuss the potential for synergistic benefits of exercise when combined with TRE. Although there is currently limited research on TRE within CR programs, we highlight CR as a unique clinical setting where TRE could play a role in secondary prevention of CVD. Overall, we outline the potential of TRE as a promising nutrition strategy to enhance the benefits of CR.

Is Lipoprotein(a) Clinically Actionable with Today's Evidence? The Answer is Yes.

PURPOSE OF REVIEW: Lipoprotein(a) is an independent risk factor for cardiovascular disease. We review the ongoing shifts in consensus guidelines for the testing and management of Lp(a) and provide insight into whether current evidence suggests that awareness and testing of Lp(a) is clinically actionable. RECENT FINDINGS: GWAS and Mendelian randomization studies have established causal links between elevated Lp(a) and forms of CVD, including CAD and calcific aortic valve disease. Testing of Lp(a) identifies patients with similar risk to that of heterozygous FH, enhances risk stratification in patients with borderline/intermediate risk as determined through traditional factors, and facilitates the assessment of inherited CVD risk through cascade screening in patients with known family history of elevated Lp(a). Reductions in Lp(a) through non-targeted therapies including PCSK9 inhibition and lipoprotein apheresis have demonstrated reductions in ASCVD risk that are likely attributable to lowering Lp(a). Targeted therapies to potently lower Lp(a) are in clinical development. Lp(a) is actionable, and can be used to identify high risk patients for primary prevention and their family members through cascade screening, and to guide intensification of therapy in primary and secondary prevention of ASCVD.

Evolving Management of Low-Density Lipoprotein Cholesterol: A Personalized Approach to Preventing Atherosclerotic Cardiovascular Disease Across the Risk Continuum.

Management of elevated low-density lipoprotein cholesterol (LDL-C) is central to preventing atherosclerotic cardiovascular disease (ASCVD) and key to reducing the risk of ASCVD events. Current guidelines on the management of blood cholesterol recommend statins as first-line therapy for LDL-C reduction according to an individual's ASCVD risk and baseline LDL-C levels. The addition of nonstatin lipid-lowering therapy to statins to achieve intensive LDL-C lowering is recommended for patients at very high risk of ASCVD events, including patients with familial hypercholesterolemia who have not achieved adequate LDL-C lowering with statins alone. Despite guideline recommendations and clinical trial evidence to support the use of lipid-lowering therapies for ASCVD risk reduction, most patients at high or very high risk do not meet LDL-C thresholds. This review explores the challenges associated with LDL-C lowering in contemporary clinical practice and proposes a framework for rethinking the binary definition of ASCVD, shifting from "primary" versus "secondary" prevention to a "continuum of risk." The approach considers the role of plaque burden and progression in subclinical disease and emphasizes the importance of early risk assessment and treatment for preventing first cardiovascular events. Patients at high risk of ASCVD events who require significant LDL-C lowering should be considered for combination therapies comprising statin and nonstatin agents. Practical guidance for the pharmacological management of elevated LDL-C, both now and in the future, is provided.

The use of ketamine infusion to dramatically reduce opioid requirements in a patient whose high-dose intrathecal opioid pump was inadvertently cut during surgery.

BACKGROUND: Chronic opioid therapy may lead to high level tolerance development, hyperalgesia, and central sensitization, which further complicates long-term therapeutic management of chronic pain patients. In this case, we encounter a patient who was receiving over 15,000 morphine milligram equivalents through their intrathecal pain pump. Unfortunately, the intrathecal pump was inadvertently cut during a spinal surgery. It was deemed unsafe to delivery IV equivalent opioid therapy in this case; instead, the patient was admitted to the ICU and given a four-day ketamine infusion. METHOD: The patient was started on a ketamine infusion at a rate of 0.5mg/kg/h, which was continued for three days. On the fourth day, the infusion rate was tapered over 12 h before being completely stopped. No coinciding opioid therapy was given during this time, which was only restarted in the outpatient setting. RESULTS: Despite chronic high levels of opioid therapy immediately prior to the ketamine infusion, the patient did not experience florid withdrawals during the infusion period. Additionally, the patient experienced remarkable improvement in their subjective pain rating, which decreased from 9 to 3-4 on an 11-point Number Rating Scale, while simultaneously being managed on an MME <100. These results were sustained through a 6-month follow-up period. CONCLUSION: Ketamine may play an important role in attenuating not only tolerance but also acute withdrawal in a setting where rapid or instant weaning from high dose chronic opioid therapy is needed.

Use of Immunization Information Systems in Ascertainment of COVID-19 Vaccinations for Claims-Based Vaccine Safety and Effectiveness Studies.

Importance: Safety and effectiveness studies of COVID-19 vaccines are being conducted using clinical data, including administrative claims. However, claims data only partially capture administered COVID-19 vaccine doses for numerous reasons, such as vaccination at sites that do not generate claims for reimbursement. Objective: To evaluate the extent to which Immunization Information Systems (IIS) data linked to claims data enhances claims-based COVID-19 vaccine capture for a commercially insured population and to estimate the magnitude of misclassification of vaccinated individuals as having unvaccinated status in the linked IIS and claims data. Design, Setting, and Participants: This cohort study used claims data from a commercial health insurance database and obtained vaccination data from IIS repositories in 11 US states. Participants were individuals younger than 65 years who resided in 1 of 11 states of interest and who were insured in health plans from December 1, 2020, through December 31, 2021. Main Outcomes and Measures: Estimated proportion of individuals with at least 1 dose of any COVID-19 vaccine and proportion of individuals with a completed vaccine series based on general population guidelines. Vaccination status estimates were calculated and compared using claims data alone and linked IIS and claims data. Remaining misclassification of vaccination status was assessed by comparing linked IIS and claims data estimates with estimates from external surveillance data sources (Centers for Disease Control and Prevention [CDC] and state Department of Health [DOH]) and capture-recapture analysis. Results: This cohort study included 5 112 722 individuals (mean [SD] age, 33.5 [17.6] years; 2 618 098 females [51.2%]) from 11 states. Characteristics of those who received at least 1 vaccine dose and those who completed a vaccine series were similar to the overall study population. The proportion with at least 1 vaccine dose increased from 32.8% using claims data alone to 48.1% when the data were supplemented with IIS vaccination records. Vaccination estimates using linked IIS and claims data varied widely by state. The percentage of individuals who completed a vaccine series increased from 24.4% to 41.9% after the addition of IIS vaccine records and varied across states. The percentages of underrecording using linked IIS and claims data were 12.1% to 47.1% lower than those using CDC data, 9.1% to 46.9% lower than the state DOH, and 9.2% to 50.9% lower than capture-recapture analysis. Conclusion and Relevance: Results of this study suggested that supplementing COVID-19 claims records with IIS vaccination records substantially increased the number of individuals who were identified as vaccinated, yet potential underrecording remained. Improvements in reporting vaccination data to IIS infrastructures could allow frequent updates of vaccination status for all individuals and all vaccines.

Trends in LDL-C following coronary angiography involving assessment by fractional flow reserve in obstructive vs non-obstructive coronary artery disease.

Background: We sought to determine whether management of LDL-C following invasive angiography and assessment by fractional flow reserve (FFR) differs between those with obstructive vs non-obstructive CAD. Methods: Retrospective study of 721 patients undergoing coronary angiography involving assessment by FFR between 2013 and 2020 at a single academic center. Groups with obstructive vs non-obstructive CAD by index angiographic and FFR findings were compared over 1 year of follow-up. Results: Based on index angiographic and FFR findings, 421 (58%) patients had obstructive CAD vs 300 (42%) with non-obstructive CAD, mean (±SD) age 66±11 years, 217 (30%) women, and 594 (82%) white. There was no difference in baseline LDL-C. At 3-months follow-up, LDL-C was lower than baseline in both groups, with no between group difference. In contrast, at 6-months, median (Q1, Q3) LDL-C was significantly higher in non-obstructive vs obstructive CAD (LDL-C 73 (60, 93) vs 63 (48, 77) mg/dL, respectively (p = 0.003), (p = 0.001 in multivariable linear regression)). At 12-months, LDL-C remained higher in non-obstructive vs obstructive CAD (LDL-C 73 (49, 86) vs 64 (48, 79) mg/dL, respectively, although not statistically significant (p = 0.104)). The rate of high-intensity statin use was lower among those with non-obstructive CAD vs obstructive CAD at all time points (p < 0.05). Conclusions: After coronary angiography involving FFR, there is intensification of LDL-C lowering at 3-months follow-up in both obstructive and non-obstructive CAD. However, by 6-months follow-up LDL-C is significantly higher among those with non-obstructive CAD vs obstructive CAD. Following coronary angiography involving FFR, patients with non-obstructive CAD may benefit from greater attention to LDL-C lowering to reduce residual ASCVD risk.

Inclisiran creates unique opportunities and challenges for patient access to therapy: early experience in a United States Lipid Clinic.

We report an early experience with inclisiran, an siRNA targeting PCSK9 administered by a healthcare professional, in an academic lipid clinic. 37 patients were prescribed inclisiran, age (mean±SD) 66±13 years, 26 (70%) women, 32 (87%) White, LDL-C 113±62 mg/dL, 18 (49%) with ASCVD and 19 (51%) with HeFH. Most patients were referred to alternate injection centers. Inclisiran was approved by insurance for 25 (68%), denied for 9 (24%), with 3 under review. While 100% of patients with Medicare obtained access to inclisiran, only 3 of 12 (25%) patients with non-Medicare insurance received approval. Approved patients were older (72±8 vs 52±13 years, p<0.001), disproportionately Medicare enrollees (88%, p<0.001), less had HeFH (40% vs 89%, p=0.019), more had ASCVD (60% vs 11%, p=0.019), less were on a statin (28% vs 78%, p=0.017), and pre-treatment LDL-C was higher (121±65 vs 77±40 mg/dL, p=0.039). These findings have implications for the future of inclisiran in the U.S. and whether inclisiran can be made more accessible, including to younger patients with non-Medicare insurance.

Secondary myoadenylate deaminase deficiency is not a common feature of inflammatory myopathies: A descriptive study.

Background: Myoadenylate deaminase (MAD) deficiency is a form of metabolic myopathy, which generally causes only mild symptoms in the primary inherited form. Inflammatory myopathies are a group of autoimmune diseases which result in skeletal muscle weakness. In addition to inflammatory pathology, it has been speculated that non-inflammatory mechanisms, and possibly secondary MAD-deficiency, may potentially contribute to weakness in these conditions. Methods: We investigated for an association between these two myopathic processes through two complementary methods. Firstly, muscle biopsy records in South Australia over a 17-year period were retrospectively reviewed for diagnosis of myositis or MAD-deficiency, as well as associated clinical features. Secondly, a prospective arm histochemically tested all incident biopsy specimens over a 12-month period for MAD-deficiency. Results: In the retrospective arm, 30 MAD-deficient cases were identified (1.3% of all biopsies), with no significant difference observed in overall rates of myositis diagnosis between patients with intact and deficient MAD activity (21.3% vs 26.7%, P = 0.47). No cases of MAD-deficiency were detected in the prospective arm, despite 39 cases of myositis being identified over this period. Conclusion: Secondary MAD deficiency is unlikely to be a major driver of symptoms in inflammatory myopathies.

Risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease.

BACKGROUNDA pilot, single-center study showed that first-degree relatives of probands with nonalcoholic fatty liver disease (NAFLD) cirrhosis have a high risk of advanced fibrosis. We aimed to validate these findings using 2 independent cohorts from the US and Europe.METHODSThis prospective study included probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least 1 first-degree relative. A total of 396 first-degree relatives - 220 in a derivation cohort and 176 in a validation cohort - were enrolled in the study, and liver fibrosis was evaluated using magnetic resonance elastography and other noninvasive imaging modalities. The primary outcome was prevalence of advanced fibrosis in first-degree relatives.RESULTSPrevalence of advanced fibrosis in first-degree relatives of probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD was 15.6%, 5.9%, and 1.3%, respectively (P = 0.002), in the derivation cohort, and 14.0%, 2.6%, and 1.3%, respectively (P = 0.004), in the validation cohort. In multivariable-adjusted logistic regression models, age of ≥50 years (adjusted OR [aOR]: 2.63, 95% CI 1.0-6.7), male sex (aOR: 3.79, 95% CI 1.6-9.2), diabetes mellitus (aOR: 3.37, 95% CI 1.3-9), and a first-degree relative with NAFLD with advanced fibrosis (aOR: 11.8, 95% CI 2.5-57) were significant predictors of presence of advanced fibrosis (all P < 0.05).CONCLUSIONFirst-degree relatives of probands with NAFLD with advanced fibrosis have significantly increased risk of advanced fibrosis. Routine screening should be done in the first-degree relatives of patients with advanced fibrosis.FUNDINGSupported by NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515, K23DK119460), NHLBI (P01HL147835), and NIAAA (U01AA029019); Academy of Finland grant 309263; the Novo Nordisk, EVO, and Sigrid Jusélius Foundations; and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 777377. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and the EFPIA.

Lipoprotein(a): Evidence for Role as a Causal Risk Factor in Cardiovascular Disease and Emerging Therapies.

Lipoprotein(a) (Lp(a)) is an established risk factor for multiple cardiovascular diseases. Several lines of evidence including mechanistic, epidemiologic, and genetic studies support the role of Lp(a) as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis/calcific aortic valve disease (AS/CAVD). Limited therapies currently exist for the management of risk associated with elevated Lp(a), but several targeted therapies are currently in various stages of clinical development. In this review, we detail evidence supporting Lp(a) as a causal risk factor for ASCVD and AS/CAVD, and discuss approaches to managing Lp(a)-associated risk.

CRABP2 - A novel biomarker for high-risk endometrial cancer.

OBJECTIVE: Investigate the clinical and functional implications of elevated CRABP2 expression in endometrial cancer (EC) patients. METHODS: Patients were stratified into high and low CRABP2 expression groups using a decision tree classifier. Univariate and multivariate statistical analyses determined the prognostic and clinicopathological consequences of increased CRABP2 expression. A CRABP2 gene signature was generated using differential expression analysis, and analyzed using network-based approaches. The findings were validated in The Clinical Proteomic Tumor Analysis Consortium (CPTAC), a newly generated cohort of 120 endometrial tissues, and The Cancer Dependency Map (DepMap). RESULTS: 60 (11%) patients in TCGA had high CRABP2 expression, whilst 468 (89%) had low expression. High expression was associated with serous EC, reduced overall survival, advanced stage and grade. Downstream retinoic acid receptors (RARG and RARA) were correlated with CRABP2 expression and were associated with worse prognosis in serous EC. The CRABP2 gene signature was enriched for Polycomb target gene sets, and was regulated by ELP3 and BMP7. BMP7 expression was increased in the CRABP2-high group, was associated with worse prognosis, and CRISPR-Cas9 screens revealed correlations in its cell-fitness score with CRABP2 following gene knockout. The opposite was true for ELP3, suggesting opposing effects from both master regulators. CONCLUSIONS: CRABP2 expression is associated with poor prognosis and advanced EC. The expression of RARA and RARG correlates with CRABP2 and are associated with worse prognosis in advanced histological subtypes. Polycomb target gene sets and two master regulators, ELP3 and BMP7, were identified as functionally relevant mechanisms driving aberrant CRABP2 expression.