Evaluation of Insulin Dosing Strategies for Hyperkalemia Management at an Academic Medical Center.

PURPOSE: While intravenous (IV) insulin is often administered at a fixed dose of 10 units for acute hyperkalemia, optimal dosing for minimizing hypoglycemia while effectively reversing hyperkalemia has not been established. The purpose of this analysis was to evaluate the effect of insulin dosing strategies on hypoglycemia in patients with hyperkalemia. METHODS: Adult patients presenting to an academic medical center who received IV insulin for hyperkalemia between 2016 and 2020 were retrospectively identified. Patients treated with 10 units of insulin (fixed) were compared to those who received < 10 units (reduced). The primary outcome was the incidence of hypoglycemia (blood glucose < 70 mg/dL) within 12 hours of insulin administration. Secondary outcomes included the incidence of severe hypoglycemia (blood glucose < 40 mg/dL) and change in potassium. Multivariable analyses were used to assess for risk factors for hypoglycemia and severe hypoglycemia. FINDINGS: Of the 2576 patients included, 305 (11.8%) received reduced dosing and 2271 (88.2%) received fixed dosing. Hypoglycemia occurred in 16.7% of the reduced group and 15.9% of the fixed group (P = 0.70). Severe hypoglycemia occurred in 2.3% of the reduced group and 2.5% of the fixed group (P = 0.86). Median potassium reduction from baseline to first check post-insulin was less with reduced dosing (-0.6 mEq/L vs -0.8 mEq/L, P < 0.001). On multivariable regression analysis, greater weight-based insulin dose and ED location were significant predictors for hypoglycemia and severe hypoglycemia. Location in the intensive care unit was associated with a decreased risk of hypoglycemia. Higher pre-insulin glucose was protective for hypoglycemia and severe hypoglycemia. IMPLICATIONS: The incidence of hypoglycemia was similar among both groups. Greater weight-based insulin dose was a significant risk factor for hypoglycemia, while higher baseline glucose levels were associated with a decreased risk, indicating that patient-specific insulin dosing for hyperkalemia may be warranted.

Guide to Lung-Protective Ventilation in Cardiac Patients.

The incidence of acute respiratory insufficiency has continued to increase among patients admitted to modern-day cardiovascular intensive care units. Positive pressure ventilation (PPV) remains the mainstay of treatment for these patients. Alterations in intrathoracic pressure during PPV has distinct effects on both the right and left ventricles, affecting cardiovascular performance. Lung-protective ventilation (LPV) minimizes the risk of further lung injury through ventilator-induced lung injury and, hence, an understanding of LPV and its cardiopulmonary interactions is beneficial for cardiologists.

Evaluation of Goal Phenytoin Levels After an Initial Intravenous Loading Dose at an Academic Medical Center.

BACKGROUND: Phenytoin intravenous loading doses are administered in status epilepticus to rapidly achieve therapeutic levels. Accurately assessing phenytoin levels after the initial load can be challenging because of its complex pharmacokinetic profile and nonstandardized weight-based loading doses. OBJECTIVES: The objectives of this analysis were to determine the incidence of patients achieving goal phenytoin levels after the initial loading dose and characterize factors that contribute to achieving the goal level. METHODS: This single-center, retrospective cohort analysis was approved by our institutional review board and included adult patients who received a phenytoin load from May 2016 to March 2021. Patients were excluded if no total phenytoin level was drawn within 24 hours of the load, if the maintenance dose was given before the first level was drawn, or if the patient was on phenytoin before the load. The major endpoint was the percentage of patients achieving a corrected goal phenytoin level of ≥10 mcg/mL after the initial load. Multivariate regression was used to determine predictors of achieving the goal phenytoin level. RESULTS: Of the 152 patients included, 139 patients (91.4%) achieved a corrected goal level after the first load. Patients at goal received a significantly higher median weight-based loading dose (19.1 mg/kg [15.0-20.0] vs 12.6 mg/kg [10.1-15.0], P < 0.01). The multivariate analysis identified weight-based dosing as a statistically significant predictor of achieving the corrected goal level (odds ratio, 1.30; 95% CI, 1.12-1.53; P < 0.01). CONCLUSION AND RELEVANCE: Most patients achieved a corrected goal phenytoin level after the initial load. A higher median weight-based loading dose was shown to be a predictor of achieving the goal level and should be encouraged for rapid seizure termination. Future studies are warranted to confirm patient-specific factors that affect rapid achievement of the goal phenytoin level.

Combining histological grade, TILs, and the PD-1/PD-L1 pathway to identify immunogenic tumors and de-escalate radiotherapy in early breast cancer: a secondary analysis of a randomized clinical trial.

BACKGROUND: The implementation of immunological biomarkers for radiotherapy (RT) individualization in breast cancer requires consideration of tumor-intrinsic factors. This study aimed to investigate whether the integration of histological grade, tumor-infiltrating lymphocytes (TILs), programmed cell death protein-1 (PD-1), and programmed death ligand-1 (PD-L1) can identify tumors with aggressive characteristics that can be downgraded regarding the need for RT. METHODS: The SweBCG91RT trial included 1178 patients with stage I-IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT, and followed for a median time of 15.2 years. Immunohistochemical analyses of TILs, PD-1, and PD-L1 were performed. An activated immune response was defined as stromal TILs ≥10% and PD-1 and/or PD-L1 expression in ≥1% of lymphocytes. Tumors were categorized as high-risk or low-risk using assessments of histological grade and proliferation as measured by gene expression. The risk of ipsilateral breast tumor recurrence (IBTR) and benefit of RT were then analyzed with 10 years follow-up based on the integration of immune activation and tumor-intrinsic risk group. RESULTS: Among high-risk tumors, an activated immune infiltrate was associated with a reduced risk of IBTR (HR 0.34, 95% CI 0.16 to 0.73, p=0.006). The incidence of IBTR in this group was 12.1% (5.6-25.0) without RT and 4.4% (1.1-16.3) with RT. In contrast, the incidence of IBTR in the high-risk group without an activated immune infiltrate was 29.6% (21.4-40.2) without RT and 12.8% (6.6-23.9) with RT. Among low-risk tumors, no evidence of a favorable prognostic effect of an activated immune infiltrate was seen (HR 2.0, 95% CI 0.87 to 4.6, p=0.100). CONCLUSIONS: Integrating histological grade and immunological biomarkers can identify tumors with aggressive characteristics but a low risk of IBTR despite a lack of RT boost and systemic therapy. Among high-risk tumors, the risk reduction of IBTR conferred by an activated immune infiltrate is comparable to treatment with RT. These findings may apply to cohorts dominated by estrogen receptor-positive tumors.

Modifiable Mechanical Ventilation Targets Are Associated With Improved Survival in Ventilated VA-ECLS Patients.

BACKGROUND: In acute respiratory distress syndrome (ARDS), lung protective ventilation (LPV) improves patient outcomes by minimizing ventilator-induced lung injury. The value of LPV in ventilated patients with cardiogenic shock (CS) requiring venoarterial extracorporeal life support (VA-ECLS) is not known, but the extracorporeal circuit provides a unique opportunity to modify ventilatory parameters to improve outcomes. OBJECTIVES: The authors hypothesized that CS patients on VA-ECLS who require mechanical ventilation (MV) may benefit from low intrapulmonary pressure ventilation (LPPV), which has the same end goals as LPV. METHODS: The authors queried the ELSO (Extracorporeal Life Support Organization) registry for hospital admissions between 2009 and 2019 for CS patients on VA-ECLS and MV. They defined LPPV as peak inspiratory pressure at 24 hours on ECLS of <30 cm H2O. Positive end-expiration pressure and dynamic driving pressure (DDP) at 24 hours were also studied as continuous variables. Their primary outcome was survival to discharge. Multivariable analyses were performed that adjusted for baseline Survival After Venoarterial Extracorporeal Membrane Oxygenation score, chronic lung conditions, and center extracorporeal membrane oxygenation volume. RESULTS: A total of 2,226 CS patients on VA-ECLS were included: 1,904 received LPPV. The primary outcome was higher in the LPPV group vs the no-LPPV group (47.4% vs 32.6%; P < 0.001). Median peak inspiratory pressure (22 vs 24 cm H2O; P < 0.001) as well as DDP (14.5 vs 16 cm H2O; P < 0.001) were also significantly lower in those surviving to discharge. The adjusted OR for the primary outcome with LPPV was 1.69 (95% CI: 1.21-2.37; P = 0.0021). CONCLUSIONS: LPPV is associated with improved outcomes in CS patients on VA-ECLS requiring MV.

Low levels of WRAP53 predict decreased efficacy of radiotherapy and are prognostic for local recurrence and death from breast cancer: a long-term follow-up of the SweBCG91RT randomized trial.

Downregulation of the DNA repair protein WD40-encoding RNA antisense to p53 (WRAP53) has been associated with radiotherapy resistance and reduced cancer survival. The aim of this study was to evaluate WRAP53 protein and RNA levels as prognostic and predictive markers in the SweBCG91RT trial, in which breast cancer patients were randomized for postoperative radiotherapy. Using tissue microarray and microarray-based gene expression, 965 and 759 tumors were assessed for WRAP53 protein and RNA levels, respectively. Correlation with local recurrence and breast cancer-related death was assessed for prognosis, and the interaction between WRAP53 and radiotherapy in relation to local recurrence was assessed for radioresistance prediction. Tumors with low WRAP53 protein levels had a higher subhazard ratio (SHR) for local recurrence [1.76 (95% CI 1.10-2.79)] and breast cancer-related death [1.55 (1.02-2.38)]. Low WRAP53 RNA levels were associated with almost a three-fold decreased effect of radiotherapy in relation to ipsilateral breast tumor recurrence [IBTR; SHR 0.87 (95% CI 0.44-1.72)] compared with high RNA levels [0.33 (0.19-0.55)], with a significant interaction (P = 0.024). In conclusion, low WRAP53 protein is prognostic for local recurrence and breast cancer-related death. Low WRAP53 RNA is a potential marker for radioresistance.

Proteogenomics decodes the evolution of human ipsilateral breast cancer.

Ipsilateral breast tumor recurrence (IBTR) is a clinically important event, where an isolated in-breast recurrence is a potentially curable event but associated with an increased risk of distant metastasis and breast cancer death. It remains unclear if IBTRs are associated with molecular changes that can be explored as a resource for precision medicine strategies. Here, we employed proteogenomics to analyze a cohort of 27 primary breast cancers and their matched IBTRs to define proteogenomic determinants of molecular tumor evolution. Our analyses revealed a relationship between hormonal receptors status and proliferation levels resulting in the gain of somatic mutations and copy number. This in turn re-programmed the transcriptome and proteome towards a highly replicating and genomically unstable IBTRs, possibly enhanced by APOBEC3B. In order to investigate the origins of IBTRs, a second analysis that included primaries with no recurrence pinpointed proliferation and immune infiltration as predictive of IBTR. In conclusion, our study shows that breast tumors evolve into different IBTRs depending on hormonal status and proliferation and that immune cell infiltration and Ki-67 are significantly elevated in primary tumors that develop IBTR. These results can serve as a starting point to explore markers to predict IBTR formation and stratify patients for adjuvant therapy.

Area Deprivation Index and Distress Community Index Scores Are Not Associated With Short-Term and Long-Term Extracorporeal Life Support Outcomes.

Distressed Communities Index (DCI) and Area Deprivation Index (ADI) are two composite ranking scores that report community level socioeconomic status (SES) by ZIP codes. The objective of this study was to evaluate the impact of SES as estimated by DCI and ADI scores on short-term and long-term outcomes after extracorporeal life support (ECLS) at a quaternary medical center. All patients on ECLS between January 1, 2015 and August 31, 2020 (N = 428) at Vanderbilt University Medical Center in Nashville, Tennessee, had their ADI and DCI scores calculated. Primary outcome was mortality during index hospitalization, and secondary outcome was survival to end of study follow-up. There was no significant difference in primary outcome between the top 25% ADI vs . bottom 75% ADI (53.8% vs . 50.6%; p = 0.56) or between top 25% DCI vs . bottom 75% DCI (56.1 vs . 49.2; p = 0.21). Adjusted odds ratio for the primary outcome with ADI and DCI was 1.13 (95% CI, 0.63-2.0; p = 0.67) and 1.28 (95% CI, 0.70-2.34; p = 0.41), respectively. Additionally, there was no significant difference in long-term survival curves based on their ADI or DCI scores. In conclusion, SES as estimated by baseline DCI and ADI scores does not appear to impact short- or long-term survival post-ECLS at a large volume center. http://links.lww.com/ASAIO/A951.

Naloxone Versus Methylnaltrexone for Opioid-Induced Constipation in Critically Ill Patients.

BACKGROUND: Opioid-induced constipation (OIC) may occur in up to 81% of critically ill patients and can lead to many complications. Opioid antagonists are a reasonable approach and may be used for managing OIC. OBJECTIVE: The purpose of this study was to assess the efficacy of enteral naloxone (NLX) versus subcutaneous methylnaltrexone (MNTX) for the management of OIC in critically ill patients. METHODS: A retrospective analysis was conducted on adult patients who received NLX or MNTX and a continuous opioid infusion for at least 48 hours. The primary end point was time to resolution of constipation, defined as hours to first bowel movement (BM) after the first dose of an opioid antagonist. Reversal of analgesia was assessed by comparing the total number of morphine milligram equivalents (MME) 24 hours preopioid and postopioid antagonist administration. Univariate and multivariate analyses were conducted to assess treatment response within 48 hours. RESULTS: Baseline characteristics were similar between patients receiving NTX (n = 89) and MNTX (n = 71). However, the time to the first BM with NLX was 18 hours compared with 41 hours with MNTX (P = 0.004). There was no difference in MME requirements 24 hours pre/post NLX or MNTX administration. Naloxone administration was identified as a statistically significant predictor of BM within 48 hours (odds ratio [OR] = 2.68 [1.33-5.38]). CONCLUSION AND RELEVANCE: The time to first BM was shorter with enteral NLX. Both NLX and MNTX appear to be effective for the management of OIC without causing reversal of analgesia. Future controlled, prospective trials comparing these agents are warranted.

Co-occurrence of Myocardial Sarcoidosis and Left Ventricular Non-compaction in a Patient with Advanced Heart Failure.

A 46-year-old man with systolic heart failure, end-stage renal disease on dialysis, ventricular tachycardia and pulmonary sarcoidosis presented with decompensated heart failure and cardiogenic shock of unknown aetiology. The hospital course was complicated by worsening shock requiring inotropic and mechanical circulatory support, as well as eventual dual heart and kidney transplantation. Cardiac imaging was used to assess the aetiology of the patient's non-ischaemic cardiomyopathy, including a PET scan and cardiac MRI. Imaging demonstrated findings consistent with left ventricular non-compaction, but was inconclusive for cardiac sarcoidosis. After eventual heart transplantation, histopathology of the patient's explanted heart showed evidence of both non-compaction and cardiac sarcoidosis. In this case report, the authors review the pathophysiology of both cardiac sarcoidosis and left ventricular non-compaction, and highlight a multimodality approach to the diagnosis of non-ischaemic cardiomyopathy.

Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma.

BACKGROUND: Acral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site. METHODS: Patients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS). RESULTS: In total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites. CONCLUSION: While the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.

Transcatheter Aortic Valve Replacement and Surgical Aortic Valve Replacement Outcomes in Left Ventricular Assist Device Patients with Aortic Insufficiency.

Background: Worsening aortic insufficiency (AI) is a known sequela of prolonged continuous-flow left ventricular assist device (LVAD) support with a significant impact on patient outcomes. While medical treatment may relieve symptoms, it is unlikely to halt progression. Surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) are among non-medical interventions available to address post-LVAD AI. Limited data are available on outcomes with either SAVR or TAVR for the management of post-LVAD AI. Methods: The National Inpatient Sample data collected for hospital admissions between the years 2015 and 2018 for patients with pre-existing continuous-flow LVAD undergoing TAVR or SAVR for AI were queried. The primary outcome of interest was a composite of in-hospital mortality, stroke, transient ischaemic attack, MI, pacemaker implantation, need for open aortic valve surgery, vascular complications and cardiac tamponade. Results: Patients undergoing TAVR were more likely to receive their procedure during an elective admission (57.1 versus 30%, p=0.002), and a significantly higher prevalence of comorbidities, as assessed by the Elixhauser Comorbidity Index, was observed in the SAVR group (29 versus 18; p=0.0001). We observed a significantly higher prevalence of the primary composite outcome in patients undergoing SAVR (30%) compared with TAVR (14.3%; p=0.001). Upon multivariable analysis adjusting for the type of admission and Elixhauser Comorbidity Index, TAVR was associated with significantly lower odds of the composite outcome (odds ratio 0.243; 95% CI [0.06-0.97]; p=0.045). Conclusion: In this nationally representative cohort of LVAD patients with post-implant AI, it was observed that TAVR was associated with a lower risk of adverse short-term outcomes compared with SAVR.

Stability of alteplase for ultrasound-facilitated catheter-directed thrombolysis.

Ultrasound-facilitated catheter-directed thrombolysis is used with low-dose alteplase to treat pulmonary embolism. This reduces the risk of bleeding that accompanies systemic administration of higher alteplase doses. Some studies suggest that alteplase given over 2 to 6 hours is safe and effective, but there are few data to support the stability of alteplase under these conditions. Therefore, we undertook this in vitro study to determine the duration of alteplase stability. Alteplase was prepared in solutions of 8 mg in 100 mL, 6 mg in 150 mL, and 8 mg in 200 mL. Solutions were administered through the EkoSonic Endovascular System (with and without ultrasound) to simulate administration over 2, 4, and 6 hours. Alteplase was assessed with reversed-phase high-performance liquid chromatography (RP-HPLC). Assays were performed at time 0 and at 30-minute intervals during simulated infusion. An enzyme-linked immunosorbent assay was used to measure alteplase concentrations at time 0 and at 15-minute intervals during simulated infusion. By using RP-HPLC in the absence of ultrasound, the alteplase concentration remained within 1% of the original concentration through 120, 240, and 360 minutes of infusion. By using RP-HPLC for measurement, alteplase in the presence of ultrasound degraded steadily over time to ∼90% of its original amount in 120 minutes, ∼80% in 240 minutes, and ∼70% in 360 minutes. The remaining alteplase was available for enzymatic activity. Alteplase solutions of 0.04 and 0.08 mg/mL degraded steadily over time during simulated ultrasound-facilitated catheter-directed administration. Alteplase that did not degrade remained available for enzymatic activity.

PD-L1 Testing in Cytological Non-Small Cell Lung Cancer Specimens: A Comparison with Biopsies and Review of the Literature.

INTRODUCTION: Programmed death-ligand 1 (PD-L1) expression is used for treatment prediction in non-small cell lung cancer (NSCLC). While cytology may be the only available material in the routine clinical setting, testing in clinical trials has mainly been based on biopsies. METHODS: We included 2 retrospective cohorts of paired, concurrently sampled, cytological specimens and biopsies. Also, the literature on PD-L1 in paired cytological/histological samples was reviewed. Focus was on the cutoff levels ≥1 and ≥50% positive tumor cells. RESULTS: Using a 3-tier scale, PD-L1 was concordant in 40/47 (85%) and 66/97 (68%) of the paired NSCLC cases in the 2 cohorts, with kappa 0.77 and 0.49, respectively. In the former cohort, all discordant cases had lower score in cytology. In both cohorts, concordance was lower in samples from different sites (e.g., biopsy from primary tumor and cytology from pleural effusion). Based on 25 published studies including about 1,700 paired cytology/histology cases, the median (range) concordance was 81-85% (62-100%) at cutoff 1% for a positive PD-L1 staining and 89% (67-100%) at cutoff 50%. CONCLUSIONS: The overall concordance of PD-L1 between cytology and biopsies is rather good but with significant variation between laboratories, which calls for local quality assurance.

MET Expression and Cancer Stem Cell Networks Impact Outcome in High-Grade Serous Ovarian Cancer.

Overexpression of the receptor tyrosine kinase MET has been linked to poor survival in several cancer types, and MET has been suggested to interact with stem cell networks. In vitro studies have further suggested a possible benefit of a combined treatment using PARP and MET inhibitors. We used a tissue microarray (TMA) with 130 samples of advanced-stage high-grade serous fallopian tube/ovarian cancer (HGSC) to investigate the prognostic value of MET protein expression alone and in combination with the stem cell factor SOX2. The possible synergistic effects of a PARP and MET inhibitor treatment were evaluated in two cell lines with BRCA1 or BRCA2 deficiency and in their BRCA1/2-proficient counterparts. Patients with tumors positive for MET had worse overall survival (log-rank test, p = 0.015) compared to patients with MET-negative tumors. The prognostic role of MET was even more prominent in the subgroup of patients with SOX2-negative tumors (p = 0.0081). No synergistic effects of the combined treatment with PARP and MET inhibitors were found in the cell lines examined. We conclude that MET expression could be used as a marker for OS in HGSC and that stemness should be taken into consideration when evaluating the mechanisms of this effect.

Intravenous levothyroxine stewardship program at a tertiary academic medical center.

PURPOSE: Based on the pharmacokinetic profile of levothyroxine, a 3-day hold guideline for adult patients ordered for intravenous (IV) levothyroxine was implemented at a tertiary academic medical center. The purpose of this study was to evaluate the impact of the implementation of an IV levothyroxine hold guideline. METHODS: This single-center, retrospective analysis identified patients ordered for IV levothyroxine during a 13-week period before and after implementation of the guideline. The primary outcome was guideline adherence, defined as full implementation of the 3-day hold. Secondary outcomes included the number of IV levothyroxine administrations avoided in the post-guideline group, extrapolated yearly cost avoidance (EYCA) after guideline implementation, reasons for guideline non-adherence, and number of safety reports involving IV levothyroxine. RESULTS: A total of 166 and 134 patients met inclusion criteria for the pre- and post-guideline groups, respectively. Guideline adherence was observed in 94 (70.1%) patients, resulting in 276 vials saved in the 13-week post-guideline period, which translated to an EYCA of $139,877. Forty orders (29.9%) were non-adherent to the guideline, with the most common reason stated as nil per os (NPO). No difference in safety outcomes was seen between the pre- and post-guideline groups, as evidenced by 1 safety report in each group. CONCLUSION: We observed a high rate of adherence to an IV levothyroxine hold guideline. This was associated with a substantial cost savings over the study period with no increase in reported safety events. To our knowledge, this is the first published report of an inpatient IV levothyroxine 3-day hold guideline.

Evaluation of Desmopressin in Critically Ill Patients with Hyponatremia Requiring 3% Hypertonic Saline.

BACKGROUND: Desmopressin (DDAVP) is often used for hyponatremia management but has been associated with increases in hospital length of stay and duration of hypertonic saline use. The purpose of this study was to evaluate hyponatremia management strategies and their effect on sodium correction in critically ill patients requiring 3% hypertonic saline (3HS). METHODS: This retrospective, single-center study included critically ill patients with hyponatremia (serum sodium ≤ 125 mEq/L) receiving 3HS from May 31 2015, to May 31 2019. Patients were divided into those who received 3HS for hyponatremia management (HTS) and those who received proactive or reactive DDAVP in addition to 3HS (D-HTS). Patients in either group could receive rescue DDAVP. The primary outcome was the percentage of patients achieving goal sodium correction of 5-10 mEq/L 24 h after 3HS initiation. RESULTS: Goal sodium correction was achieved in 52.5% of patients in HTS compared to 65.6% of patients in D-HTS (p = 0.21). Patients in HTS had a shorter duration of 3HS infusion (p = 0.0022) with no difference in ICU length of stay, free water intake, urine output, or serum sodium increases 12 and 24 h after receiving 3HS. Overcorrection during any 24- or 48 h period was not statistically different between groups. CONCLUSION: Patients in HTS and D-HTS had similar rates of achieving goal sodium correction at 24 h. A proactive or reactive DDAVP strategy led to an increase in 3HS duration and total amount with no significant difference in rates of overcorrection. Prospective, randomized studies assessing standardized strategies for hyponatremia management and DDAVP administration are warranted.

Proteogenomic Workflow Reveals Molecular Phenotypes Related to Breast Cancer Mammographic Appearance.

Proteogenomic approaches have enabled the generat̲ion of novel information levels when compared to single omics studies although burdened by extensive experimental efforts. Here, we improved a data-independent acquisition mass spectrometry proteogenomic workflow to reveal distinct molecular features related to mammographic appearances in breast cancer. Our results reveal splicing processes detectable at the protein level and highlight quantitation and pathway complementarity between RNA and protein data. Furthermore, we confirm previously detected enrichments of molecular pathways associated with estrogen receptor-dependent activity and provide novel evidence of epithelial-to-mesenchymal activity in mammography-detected spiculated tumors. Several transcript-protein pairs displayed radically different abundances depending on the overall clinical properties of the tumor. These results demonstrate that there are differentially regulated protein networks in clinically relevant tumor subgroups, which in turn alter both cancer biology and the abundance of biomarker candidates and drug targets.