Role of epigenetic regulation on catecholamine synthesis in pheochromocytoma and paraganglioma.

INTRODUCTION: Pheochromocytomas and paragangliomas (PPGLs) typically secrete catecholamines and their metabolites (metanephrines [MN] and normetanephrine [NMN]). Catecholamines are synthesized by several enzymes: phenylalanine hydroxylase (encoded by PAH), tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (DDC), dopamine ß-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT). MN/NMN secretion varies between anatomical and molecular subgroups. The aim of this study was to assess the correlation between DNA methylation of catecholamine synthesis genes and MN/NMN secretion. METHODS: Gene promoter methylation of PAH, TH, AADC, DBH, and PNMT were extracted and calculated based on publicly available data. Comparisons and correlation analysis were performed between MN ± NMN (MN/NMN), NMN only, and neither/unknown secretion patterns. Methylation levels and MN/NMN patterns were compared by three genetic alteration subgroups: pseudohypoxia (PH), kinase signaling (KS), and others. RESULTS: A total of 178 cases were included. Methylation of PAH CpGs negatively correlated with probability for MN/NMN secretion (p < .05 for all CpGs) and positively with NMN-only secretion. NMN-only secreting tumors had significantly higher promoter methylation of PAH, DBH, and PNMT compared with MN/NMN-secreting tumors. MN/NMN-secreting PPGLs had mainly KS alterations (52.1%), whereas NMN-only PPGLs had PH alterations (41.9%). PPGLs in the PH versus KS group had gene promoter hypermethylation of PAH (p = .002), DBH (p = .02), and PNMT (p = .003). CONCLUSIONS: Promoter methylation of genes encoding catecholamine synthesis enzymes is strongly and inversely correlated with MN/NMN patterns in PPGLs. KS and PH-related tumors have distinct methylation patterns. These results imply that methylation is a key regulatory mechanism of catecholamine synthesis in PPGLs.

Assessing Health-Related Quality of Life in Non-Directed Versus Directed Kidney Donors: Implications for the Promotion of Non-Directed Donation.

Living kidney donation has increased significantly, but little is known about the post-donation health-related quality of life (HRQoL) of non-directed donors (NDs) vs. directed donors (DDs). We thus examined the outcomes of 112 living kidney donors (82 NDs, 30 DDs). For the primary outcomes-namely, the mean physical component summary (PCS) and mental component summary (MCS) scores of the 12-item Short Form Survey (SF-12) questionnaire-scores were significantly higher for the NDs vs. the DDs (PCS: +2.69, MCS: +4.43). For secondary outcomes, NDs had shorter hospital stays (3.4 vs. 4.4 days), returned to physical activity earlier (45 vs. 60 days), exercised more before and after donation, and continued physical activity post-donation. Regression analyses revealed that donor type and white blood cell count were predictive of the PCS-12 score, and donor type was predictive of the MCS-12 score. Non-directed donation was predictive of a shorter hospital stay (by 0.78 days, p < 0.001) and the odds of having PCS-12 and MCS-12 scores above 50 were almost 10 and 16 times higher for NDs, respectively (p < 0.05). These findings indicate the safety and potential benefits of promoting non-directed donation. However, careful selection processes must be maintained to prevent harm and exploitation.

Predictors and Adverse Outcomes of Acute Kidney Injury in Hospitalized Renal Transplant Recipients.

Data about in-hospital AKI in RTRs is lacking. We conducted a retrospective study of 292 RTRs, with 807 hospital admissions, to reveal predictors and outcomes of AKI during admission. In-hospital AKI developed in 149 patients (51%). AKI in a previous admission was associated with a more than twofold increased risk of AKI in subsequent admissions (OR 2.13, p < 0.001). Other major significant predictors for in-hospital AKI included an infection as the major admission diagnosis (OR 2.93, p = 0.015), a medical history of hypertension (OR 1.91, p = 0.027), minimum systolic blood pressure (OR 0.98, p = 0.002), maximum tacrolimus trough level (OR 1.08, p = 0.005), hemoglobin level (OR 0.9, p = 0.016) and albumin level (OR 0.51, p = 0.025) during admission. Compared to admissions with no AKI, admissions with AKI were associated with longer length of stay (median time of 3.83 vs. 7.01 days, p < 0.001). In-hospital AKI was associated with higher rates of mortality during admission, almost doubled odds for rehospitalization within 90 days from discharge and increased the risk of overall mortality in multivariable mixed effect models. In-hospital AKI is common and is associated with poor short- and long-term outcomes. Strategies to prevent AKI during admission in RTRs should be implemented to reduce re-admission rates and improve patient survival.

The association between adrenal adenoma size, autonomous cortisol secretion and metabolic derangements.

OBJECTIVE: Autonomous cortisol secretion (ACS) is common in patients with adrenal incidentalomas (AI). ACS is associated with increased cardiovascular morbidity and mortality. Data regarding the association between radiological characteristics of adrenal adenomas, their hormonal functionality and metabolic outcomes, are scarce and inconclusive. In this study, we aim to delineate the association between radiological characteristics of AI, ACS and metabolic status. METHODS: A cross-sectional study of 77 patients with AI who underwent a comprehensive hormonal evaluation. Radiological assessments were performed by an independent radiologist blinded to the clinical and hormonal phenotype of each case. Linear regression models were used to evaluate the association between post dexamethasone suppression test (DST) cortisol levels, metabolic indices and radiological measurements. RESULTS: Mean maximal adenoma diameter was greater in patients with versus without ACS (20.35 ± 6 vs. 27.09 ± 9.3 mm, respectively, p < .01). Maximal adenoma diameter was found to be positively and linearly correlated with post-DST morning cortisol levels across their entire range (R = .474, p < .01). Linear correlations between maximal adenoma diameter and indices of glycemic control showed a correlation coefficient (R) of .481 and .463 for fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c), respectively, p < .01. When analysis included only patients with ACS, an R = .584 and R = .565 was observed for FPG and HbA1c, respectively (p < .01 for both). The association between maximal adenoma diameter and both FPG and post-DST morning cortisol intensified in patients with metabolic syndrome. CONCLUSION: There is a quantitative positive mild correlation between AI size and both cortisol autonomy and metabolic parameters.

The Use of Brain Natriuretic Peptide as a Decision-supporting Tool in Hospitalized Patients.

BACKGROUND: Most dyspneic patients in internal medicine departments have co-morbidities that interfere with the clinical diagnosis. The role of brain natriuretic peptide (BNP) levels is well-established in the acute setting but not in hospitalized patients. OBJECTIVES: To evaluate the additive value of BNP tests in patients with dyspnea admitted to medical wards who did not respond to initial treatment. METHODS: We searched the records of patients who were hospitalized in the department of internal medicine D at Sheba Medical Center during 2012 and were tested for BNP in the ward. Data collected included co-morbidity, medical treatments, diagnosis at presentation and discharge, lab results including BNP, re-hospitalization, and mortality at one year following hospitalization. RESULTS: BNP results were found for 169 patients. BNP was taken 1.7 ± 2.7 days after hospitalization. According to BNP levels, dividing the patients into tertiles revealed three equally distributed groups with a distinctive character. The higher tertile was associated with higher rates of cardiac co-morbidities, including heart failure, but not chronic obstructive pulmonary disease. Higher BNP levels were related to one-year re-hospitalization and mortality. In addition, higher BNP levels were associated with higher rates of in-admission diagnosis change. CONCLUSIONS: BNP levels during hospitalization in internal medicine wards are significantly related to cardiac illness, the existence of heart failure, and patient prognosis. Thus, BNP can be a useful tool in managing dyspneic patients in this setting.

Distinct Prognostic Factors in Sporadic and Multiple Endocrine Neoplasia Type 1-Related Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PNET) may develop sporadically or in the context of hereditary syndromes. In patients with multiple endocrine neoplasia type 1 (MEN1), PNET is the leading cause of death. Our aim was to compare the mortality risk in sporadic and MEN1-related PNETs and identify high-risk populations. A retrospective Surveillance, Epidemiology, and End Results database analysis of patients with PNET was used. Patients with MEN1 were defined by syn/metachronous pituitary adenoma. Clinical data were retrieved, and all-cause mortality (ACM) risk was compared in univariate and multivariable analyses. The cohort included 569 patients (46.6% males) with sporadic (n=542) and MEN1-related (n=27) PNETs. Age at diagnosis of MEN1-related PNET was significantly younger than with sporadic PNETs (mean age 49.2±16.7 vs. 61.6±12.7 years, respectively; p < 0.001). Survival analysis showed a trend for a better outcome in patients with MEN1-related vs. sporadic PNET (Log-rank, p=0.09) and in subgroup analysis for patients with advanced disease (p=0.08). Furthermore, among patients followed expectantly, those with MEN1-related PNET had lower ACM risk than their sporadic counterparts (p=0.08). Multivariable analysis demonstrated lower ACM risk in patients diagnosed with MEN1 (hazard ratio 0.35, 95% confidence interval 0.11-1.2, p=0.09), further supporting the trend detected in the univariate analysis. In conclusion, our study demonstrates the distinct clinical profile of patients with MEN1-related PNET compared to sporadic disease and emphasizes the expertise required to accurately manage patients with PNET in this rare context. The cautious decision-making required before embarking on surgical intervention is further emphasized in this robust analysis of a large cancer database.

The urologist's learning curve of "in-bore" magnetic resonance-guided prostate biopsy.

BACKGROUND: The combination of multi-parametric MRI to locate and define suspected lesions together with their being targeted by an MRI-guided prostate biopsy has succeeded in increasing the detection rate of clinically significant disease and lowering the detection rate of non-significant prostate cancer. In this work we investigate the urologist's learning curve of in-bore MRI-guided prostate biopsy which is considered to be a superior biopsy technique. MATERIALS AND METHODS: Following Helsinki approval by The Chaim Sheba Medical Center ethics committee in accordance with The Sheba Medical Center institutional guidelines (5366-28-SMC) we retrospectively reviewed 110 IB-MRGpBs performed from 6/2016 to 1/2019 in a single tertiary center. All patients had a prostate multi-parametric MRI finding of at least 1 target lesion (prostate imaging reporting and data system [PI-RADS] score ≥ 3). We analyzed biopsy duration and clinically significant prostate cancer detection of targeted sampling in 2 groups of 55 patients each, once by a urologist highly trained in IB-MRGpBs and again by a urologist untrained in IB-MRGpBs. These two parameters were compared according to operating urologist and chronologic order. RESULTS: The patients' median age was 68 years (interquartile range 62-72). The mean prostate-specific antigen level and prostate size were 8.6 ± 9.1 ng/d and 53 ± 27 cc, respectively. The mean number of target lesions was 1.47 ± 0.6. Baseline parameters did not differ significantly between the 2 urologists' cohorts. Overall detection rates of clinically significant prostate cancer were 19%, 55%, and 69% for PI-RADS 3, 4 and 5, respectively. Clinically significant cancer detection rates did not differ significantly along the timeline or between the 2 urologists. The average duration of IB-MRGpB targeted sampling was 28 ± 15.8 min, correlating with the number of target lesions (p < 0.0001), and independent of the urologist's expertise. Eighteen cases defined the cutoff for the procedure duration learning curve (p < 0.05). CONCLUSIONS: Our data suggest a very short learning curve for IB-MRGpB-targeted sampling duration, and that clinically significant cancer detection rates are not influenced by the learning curve of this technique.

Normal-range emergency department serum phosphorus levels and all-cause mortality.

PURPOSE OF THE STUDY: Hypophosphataemia and hyperphosphataemia are frequently encountered in hospitalised patients and are associated with significant clinical consequences. However, the prognostic value of normal-range phosphorus levels on all-cause mortality and hospitalisations is not well established. Therefore, we examined the association between normal-range phosphorus levels, all-cause mortality and hospitalisations in patients presenting to the emergency department of a tertiary medical centre in Israel. STUDY DESIGN: A retrospective analysis of patients presenting to the Chaim Sheba Medical Center emergency department between 2012 and 2018. The cohort was divided into quartiles based on emergency department phosphorus levels: 'very-low-normal' (p ≥ 2 mg/dL and p ≤ 2.49 mg/dL), 'low-normal' (p ≥ 2.5 mg/dL and p ≤ 2.99 mg/dL), 'high-normal' (p≥  3 mg/dL and p≤3.49 mg/dL) and 'very-high-normal' (p ≥  3.5 mg/dL and p ≤ 4 mg/dL). We analysed the association between emergency department phosphorus levels, hospitalisation rate and 30-day and 90-day all-cause mortality. RESULTS: Our final analysis included 223 854 patients with normal-range phosphorus levels. Patients with 'very-low-normal' phosphorus levels had the highest mortality rate. Compared with patients with 'high-normal' phosphorus levels, patients with 'very-low-normal' levels had increased 30-day all-cause mortality (OR 1.3, 95% CI 1.1 to 1.4, p<0.001), and increased 90-day all-cause mortality (OR 1.2, 95% CI 1.1 to 1.3, p<0.001). Lower serum phosphorus levels were also associated with a higher hospitalisation rate, both for the internal medicine and general surgery wards (p<0.001). CONCLUSIONS: Lower phosphorus levels, within the normal range, are associated with higher 30-day and 90-day all-cause mortality and hospitalisation rate.

The Quantitative Relationship Between Autonomous Cortisol Secretion, Dysglycemia and the Metabolic Syndrome.

OBJECTIVE: Autonomous cortisol secretion (ACS) is the most common endocrine abnormality in the evaluation of adrenal incidentalomas. The categorization of ACS is derived from a 1 mg dexamethasone suppression test (DST). Impaired DST is associated with several metabolic derangements. In this study we analyzed the association between post-DST cortisol level, analyzed as a continuous parameter, and indices of glycemic metabolism. METHODS: We prospectively collected data of 1,976 patients evaluated for adrenal incidentalomas in a large tertiary medical center between December 1, 2017, and August 31, 2019. Seventy-three patients completed the evaluation process. Post-DST cortisol levels were analyzed for correlation with various metabolic parameters, including fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) among the general cohort and for subgroups stratified by the number of metabolic syndrome (MS) criteria. RESULTS: Post-DST cortisol demonstrated a linear association with FPG and HbA1c across its entire cortisol range (R = 0.51 and 0.41, respectively; P≤.01). The association between post-DST cortisol and FPG was strengthened with an increased number of metabolic syndrome criteria. Patients with 4 MS criteria show a stronger association (R = 0.92) compared to patients with only a single criterion (R = 0.509). Furthermore, mean post-DST cortisol levels increased as the number of MS criteria accumulated. CONCLUSION: Post-DST cortisol should be viewed as a continuous parameter in risk stratification algorithms for the development of MS and particularly dysglycemia.

The association between fasting plasma glucose and glycated hemoglobin in the prediabetes range and future development of hypertension.

BACKGROUND: Prediabetes is a well-established risk factor for progression to overt diabetes mellitus (DM), which is in turn associated with development of hypertension (HTN) and vice versa. However, the role of prediabetes and HbA1c in particular as an independent risk factor for the development of hypertension is unclear. AIM: In this current study, we aimed to evaluate the association between both fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) levels in the prediabetes range and development of HTN among a large cohort of normotensive subjects. DESIGN AND METHODS: We investigated 5016 normotensive participants without DM and other cardiovascular risk factors who were annually screened in a tertiary medical center. Subjects were divided into normoglycemic and prediabetic groups. Normoglycemia was defined as HbA1c < 5.7% and FPG < 100 mg/dl. Prediabetes was defined according to the ADA criteria, i.e., 6.5% > HbA1c ≥ 5.7% or impaired fasting glucose (IFG):126 mg/dl > FPG ≥ 100 mg/dl. Subgroup analysis was made by dividing participants into four groups according to FPG and HbA1C levels, i.e., normoglycemia, impaired HbA1c only, IFG only, and both parameters impaired. RESULTS: During a follow-up of 3.7 ± 2.9 years, 318 (6.3%) subjects developed HTN. A cumulative hazard function for the development of hypertension showed a 2.89-fold ([95% CI 2.19-3.83], p < .0001) increased risk for HTN in the prediabetic population. In a multivariable Cox proportional hazard regression model adjusted to common confounding risk factors for HTN, prediabetes was found to be independently associated with a 1.95-fold ([95%, CI 1.43-2.52] p < .0001) increased risk for hypertension. Impaired HbA1C only was not found to be independently associated with HTN, while IFG only showed a 2.13-fold (95%, [CI 1.46-3.11] p < .0001) increased risk for HTN compared to normoglycemic, and a 2.55-fold ([95% CI 1.85-3.51] p < .0001) increased risk for HTN when both parameters impaired. CONCLUSION: Our study demonstrates that FPG in the prediabetes range, albeit not glycated hemoglobin, is independently and significantly associated with future development of HTN. Therefore, our findings further highlight the pivotal predictive role of IFG for HTN development as opposed to the limited independent role of abnormal HbA1c levels.

Renal glucosuria is associated with lower body weight and lower rates of elevated systolic blood pressure: results of a nationwide cross-sectional study of 2.5 million adolescents.

BACKGROUND: Gene coding mutations found in sodium glucose co-transporters (SGLTs) are known to cause renal glucosuria. SGLT2 inhibitors have recently been shown to be effective hypoglycemic agents as well as possessing cardiovascular and renal protective properties. These beneficial effects have to some extent, been attributed to weight loss and reduced blood pressure. The aim of the current study was to evaluate the prevalence of renal glucosuria amongst a large cohort of Israeli adolescents and to investigate whether renal glucosuria is associated with lower body weight and lower blood pressure values. METHODS: Medical and socio-demographic data were collected from the Israeli Defense Force's conscription center's database. A cross-sectional study to evaluate the association between conscripts diagnosed as overweight [BMI percentiles of ≥ 85 and < 95 and obesity (≥ 95 BMI percentile)] and afflicted with renal glucosuria was conducted. In addition, we assessed the association of renal glucosuria with elevated diastolic and systolic blood pressure. Multinomial regression models were used. RESULTS: The final study cohort comprised 2,506,830 conscripts of whom 1108 (0.044%) were diagnosed with renal glucosuria, unrelated to diabetes mellitus, with males twice as affected compared to females. The adjusted odds ratio for overweight and obesity was 0.66 (95% CI 0.50-0.87) and 0.62 (95% CI 0.43-0.88), respectively. Adolescents afflicted with renal glucosuria were also less likely to have an elevated systolic blood pressure of 130-139 mmHg with an adjusted odds ratio of 0.74 (95% CI 0.60-0.90). CONCLUSIONS: Renal glucosuria is associated with lower body weight and obesity as well as with lower rates of elevated systolic blood pressure.

Interleukin-1α deficiency attenuates endoplasmic reticulum stress-induced liver damage and CHOP expression in mice.

BACKGROUND & AIMS: ER stress promotes liver fat accumulation and induction of inflammatory cytokines, which contribute to the development of steatohepatitis. Unresolved ER stress upregulates the pro-apoptotic CHOP. IL-1α is localized to the nucleus in apoptotic cells, but is released when these cells become necrotic and induce sterile inflammation. We investigated whether IL-1α is involved in ER stress-induced apoptosis and steatohepatitis. METHODS: We employed WT and IL-1α-deficient mice to study the role of IL-1α in ER stress-induced steatohepatitis. RESULTS: Liver CHOP mRNA was induced in a time dependent fashion in the atherogenic diet-induced steatohepatitis model, and was twofold lower in IL-1α deficient compared to WT mice. In the ER stress-driven steatohepatitis model, IL-1α deficiency decreased the elevation in serum ALT levels, the number of apoptotic cells (measured as caspase-3-positive hepatocytes), and the expression of IL-1ß, IL-6, TNFα, and CHOP, with no effect on the degree of fatty liver formation. IL-1α was upregulated in ER-stressed-macrophages and the protein was localized to the nucleus. IL-1ß mRNA and CHOP mRNA and protein levels were lower in ER-stressed-macrophages from IL-1α deficient compared to WT mice. ER stress induced the expression of IL-1α and IL-1ß also in mouse primary hepatocytes. Recombinant IL-1α treatment in hepatocytes did not affect CHOP expression but upregulated both IL-1α and IL-1ß mRNA levels. CONCLUSION: We show that IL-1α is upregulated in response to ER stress and IL-1α deficiency reduces ER stress-induced CHOP expression, apoptosis and steatohepatitis. As a dual function cytokine, IL-1α may contribute to the induction of CHOP intracellularly, while IL-1α released from necrotic cells accelerates steatohepatitis via induction of inflammatory cytokines by neighboring cells.

High-risk type-2 diabetes mellitus patients, without prior ischemic events, have normal blood platelet functionality profiles: a cross-sectional study.

BACKGROUND: Patients with type 2 diabetes mellitus (DM) display a predisposition for vascular disease. Platelets taken from vasculopathic diabetic patients, show enhanced stimuli-induced activation and aggregation responses. Aspirin remains the cornerstone antiplatelet agent for secondary prevention of vascular complications among diabetic patients, yet evidence of its efficacy and safety in primary prevention are conflicting. Our aim was to assess whether high risk diabetic patients, without previous ischemic events, have abnormal platelet functionality profiles. METHODS: The study included 82 diabetic patients and 86 matched non-diabetic patients without prior ischemic events nor treatment with anti-platelet medications. Blood samples were analyzed for platelet markers of activation, turnover and leukocyte-platelet interactions. RESULTS: Our final analysis included 122 males (74 %), with a mean age of 61 years. Mean platelet volume (MPV) was similar between the diabetic patients and controls (9.2 fL for both). Following activation, PAC-1 binding and P-selectin expression were found comparable between the diabetic patients and controls (83 % versus 81 % and 76 % versus 74 %, respectively). Leukocyte-platelet aggregates (LPAs) were similar between the diabetic patients and controls (18 % versus 17 %, respectively). Neutrophil-platelet aggregates (NPAs) and monocyte-platelet aggregates (MPAs) were also found similar in the diabetic patients and controls. Elevated fasting plasma glucose was associated with increased LPAs rates. CONCLUSIONS: High risk type-2 diabetes mellitus patients, without prior ischemic events, have normal blood platelet functionality profiles.

Knockdown of interleukin-1α does not attenuate LPS-induced production of interleukin-1ß in mouse macrophages.

IL-1α and IL-1ß are synthesized as 31kDa cell-associated precursors following TLR-4 stimulation, but their processing to the mature form and secretion require a second intracellular stimulus. The unique localization of the precursor of IL-1α (pro-IL-1α) to the nucleus suggested a role in transcriptional regulation of inflammatory cytokines. We explored the hypothesis that pro-IL-1α is involved in regulation of IL-1ß expression following TLR-4 stimulation. IL-1ß mRNA and protein levels were specifically decreased in macrophages from IL-1α-deficient mice following TLR-1/2, TLR-4 or TLR-9 stimulation, supporting the hypothesis. However, activation of the main upstream regulators of IL-1ß expression, IRF3, NFkB and p38/JNK, were not reduced in macrophages from IL-1α-deficient mice. In order to assess the specific role of IL-1α in macrophages, we generated mice with myeloid cell deficiency of IL-1α (LyzMCre-loxp). Despite over 90% knockdown of IL-1α, TLR-4 stimulated macrophages from LyzMCre-loxp mice did not produce lower levels of IL-1ß compared to IL-1α-loxp-flanked mice. In order to overcome the possibility that effects are caused by the incomplete deficiency of IL-1α, we generated new whole-body IL-1α knockout mice (GeneralCre-IL-1α) and the findings were similar to myeloid cell-deficient IL-1α. Collectively, our findings do not support the previously suggested role of nuclear IL-1α in gene regulation of IL-1ß. Rather, they suggest that IL-1α acts mainly as an alarmin that is sequestered in the nucleus following stimulation with TLR-4.

[Dyspnea, hypoxia and a confusional state--a post-recovery diagnosis].

We present a case of a 48 year old female, with a medical history significant for paraplegia due to a cervical cord injury and a history of transitional cell carcinoma, which necessitated a urinary bladder ileal reconstruction. The patient was hospitalized due to an acute confusional state, severe respiratory distress and hemolytic anemia. One day prior to hospitalization, she was involved in a minor motor vehicle accident, yet she and her family denied any injuries due to the accident and the patient did not complain of pain. During the course of her hospitalization the patient was febrile, yet we did not find any evidence of an infectious cause for her symptoms. Notably, lumbar puncture and MRI scan were relatively contraindicated, hence a CNS infection was not completely ruled out. We also thoroughly investigated her respiratory symptoms, but could not reach a conclusive diagnosis. Nevertheless, after approximately 14 days of diagnostic efforts, empirical antibiotic treatment and supportive care, all clinical and laboratory abnormalities had resolved. The patient was discharged with a presumed diagnosis of a poorly understood infectious process. However, not long after, she returned to the emergency department complaining of a red, painful, swollen right knee. Imaging studies demonstrated a right supracondylar as well as a tibial plateau fracture. Consequently, a post-recovery diagnosis of fat emboli syndrome was made.

Non-Interventional Weight Changes Are Associated with Alterations in Serum Uric Acid Levels.

Background/Objectives: Serum uric acid is an established cardiovascular risk factor. Higher serum uric acid levels are associated with overweight and obesity. We assessed whether non-interventional weight changes affect serum uric acid levels. Methods: We performed a retrospective analysis of 19,193 participants referred to annual medical screening. Body mass index (BMI) and serum uric acid were measured annually. Subjects were divided into five groups according to changes in BMI between visits: large reduction (reduction of more than 5% in BMI), moderate reduction (reduction of more than 2.5% and 5% or less in BMI), unchanged (up to 2.5% change in BMI), moderate increase (increase of more than 2.5% and 5% or less in BMI), and large increase (increase of more than 5% in BMI). The primary outcome was serum uric acid level changes between visits. Results: A decrease in serum uric acid levels was evident as BMI decreased and an increase in serum uric acid levels was associated with an increase in BMI. The proportion of patients whose serum uric acid levels were increased by at least 10% between visits increased with the relative increase in BMI, while the proportion of patients whose serum uric acid levels were reduced by at least 10% decreased with the relative decrease in BMI. Conclusions: Non-interventional weight changes, even modest, are associated with significant alterations in serum uric acid levels. Our findings may aid in better risk stratification and the primary prevention of cardiovascular morbidity and mortality.

A 120-Minute Saline Infusion Test for the Confirmation of Primary Aldosteronism: A Pilot Study.

BACKGROUND: The saline infusion test (SIT) to confirm primary aldosteronism requires infusing 2 L of normal saline over 240 minutes. Previous studies raised concerns regarding increased blood pressure and worsening hypokalemia during SIT. We aimed to evaluate the diagnostic applicability of a SIT that requires 1 L of saline infusion over 120 minutes. METHODS: A cross-sectional study, including all patients in a large medical center who underwent SIT from 1 January 2015 to 30 April 2023. Blood samples were drawn for baseline renin and aldosterone (t = 0) after 2 hours (t = 120 min) and after 4 hours (t = 240 min) of saline infusion. We used ROC analysis to evaluate the sensitivity and specificity of various aldosterone cut-off values at t = 120 to confirm primary aldosteronism. RESULTS: The final analysis included 62 patients. A ROC analysis yielded 97% specificity and 90% sensitivity for a plasma aldosterone concentration (PAC) of 397 pmol/L (14 ng/dL) at t = 120 to confirm primary aldosteronism, and an area under the curve of 0.97 (95% CI [0.93, 1.00], P < 0.001). Almost half (44%) of the patients did not suppress PAC below 397 pmol/L (14 ng/dL) at t = 120. Of them, only one (4%) patient suppressed PAC below 276 pmol/L (10 ng/dL) at t = 240. Mean systolic blood pressure increased from 140.1 ±â€…21.3 mm Hg at t = 0 to 147.6 ±â€…14.5 mm Hg at t = 240 (P = 0.011). CONCLUSIONS: A PAC of 397 pmol/L (14 ng/dL) at t = 120 has high sensitivity and specificity for primary aldosteronism confirmation.

Non-Interventional Weight Changes Are Associated with Alterations in Lipid Profiles and in the Triglyceride-to-HDL Cholesterol Ratio.

BACKGROUND: Obesity is associated with dyslipidemia, and weight loss can improve obese patients' lipid profile. Here, we assessed whether non-interventional weight changes are associated with alterations in lipid profile, particularly the triglyceride (TG)-to-high-density lipoprotein cholesterol (HDL-C) ratio (TG/HDL-C). METHODS: In this retrospective analysis of subjects referred to medical screening, body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), TG, and HDL-C levels were measured annually. Patients were divided according to BMI changes between visits. The primary outcomes were the changes in LDL-C, TG, HDL-C, and the TG/HDL-C ratio between visits. RESULTS: The final analysis included 18,828 subjects. During the year of follow-up, 9.3% of the study population lost more than 5% of their weight and 9.2% gained more than 5% of their weight. The effect of weight changes on TG and on the TG/HDL-C ratio was remarkable. Patients with greater BMI increases showed greater increases in their TG/HDL-C ratio, and conversely, a decreased BMI level had lower TG/HDL-C ratios. This is true even for moderate changes of more than 2.5% in BMI. CONCLUSIONS: Non-interventional weight changes, even modest ones, are associated with significant alterations in the lipid profile. Understanding that modest, non-interventional weight changes are associated with alterations in the TG/HDL-C ratio may aid in better risk stratification and primary prevention of CV morbidity and mortality.

Elevated International Normalized Ratio and Mortality in Hospitalized Patients Treated with Direct Oral Anticoagulants.

BACKGROUND: Direct oral anticoagulants (DOACs) are associated with a prolongation of the prothrombin time and an increased international normalized ratio (INR). The clinical significance of these changes is unclear. This study aimed to examine the association between an elevated INR on admission and in-hospital death and long-term survival in patients treated with DOACs. METHODS: Data were retrospectively retrieved from records of hospitalized patients at the Sheba Medical Center between November 2008 and July 2023. Patients were selected based on DOAC treatment, coagulation profile, and INR test done within 48 hours of hospitalization. The outcomes were in-hospital mortality and mortality in the year following hospitalization. RESULTS: The study included 11,399 hospitalized patients treated with DOACs. Patients with elevated INR had a 180% higher risk of in-hospital mortality (adjusted odds ratio 2.80; 95% confidence interval, 2.30-3.39) and a 57% increased risk of death during the following year (adjusted hazard ratio 1.57; 95% confidence interval, 1.44-1.71). Similar results were observed in subgroup analyses for each DOAC. CONCLUSIONS: An elevated INR on admission is associated with a higher risk for in-hospital death and increased risk for mortality during the first year following hospitalization in hospitalized patients treated with DOACs. This highlights that elevated INR levels in patients on DOACs should not be dismissed as laboratory variations due to DOAC treatment, as they may serve as a prognostic marker.

Should we change the target blood pressure in diabetic patients?

Hypertension is a major modifiable risk factor for cardiovascular morbidity and mortality in diabetic patients. Guidelines recommend lowering blood pressure (BP) to less than 130/80 mmHg in diabetic patients. These recommendations are based on several studies in diabetic patients that showed the benefit of intensive BP control. However in all the studies the achieved BP was higher than 130/80 mmHg. Re-evaluation of earlier studies, as well as more recently accumulated data suggest that intensive BP control is associated with a significant reduction in all-cause mortality and stroke rate, but with no benefit for other microvascular or macrovascular (cardiac, renal and retinal) outcomes. Intensive BP control is associated with an increased risk of serious adverse effects, particularly for systolic BPs levels lower than 130 mmHg. When determining the target BP in diabetic patients one should balance the potential cerebrovascular protection against the increased risk of serious side effects, and the absence of benefit for other circulatory system. It seems therefore, that lowering BP to levels close to 130/80 mmHg should be the main goal of treatment in diabetic patients.