Early Reexploration for Bleeding Is Associated With Improved Outcome in Cardiac Surgery.

BACKGROUND: Reexploration after cardiac surgery, most frequently for bleeding, is a quality metric used to assess surgical performance. This may cause surgeons to delay return to the operating room in favor of attempting nonoperative management. This study investigated the impact of the timing of reexploration on morbidity and mortality. METHODS: This study was a single-institution retrospective review of all adult cardiac surgery patients from July 2010 to June 2020. Time to reexploration was assessed, and outcomes were compared across increasing time intervals. Reported bleeding sites were classified into 5 groups, and bleeding rate (chest tube output) was compared across bleeding sites. Univariable analysis was performed using the Fisher exact and Kruskal-Wallis tests. Multivariable logistic regression models were used for risk-adjusted analyses. RESULTS: Of 10 070 eligible patients, 251 (2.5%) required reexploration for postoperative bleeding. The most common site of bleeding was "any suture line" (n = 70; 28%). Interestingly, in 30% of cases (n = 75) "no active bleeding" site was reported. The highest rate of bleeding (mL/h) was observed in the "any mediastinal structure" group (median, 450; interquartile range [IQR], 185, 8878), and the lowest rate was noted in the "no active bleeding" group (median, 151.2; IQR, 102, 270). Both morbidity rates (0-4 hours, 12.3% vs 25-48 hours, 37.5%; P = .001) and mortality rates (0-4 hours, 3.1% vs 25-48 hours, 43.8%; P = .001) escalated significantly with increasing time to reexploration. CONCLUSIONS: Delayed reexploration for bleeding after cardiac surgery is associated with increased risk for morbidity and mortality. Early surgical intervention, particularly within 4 hours, may improve outcomes. Implications from using reoperation as a performance metric may lead to unnecessary delay and patient harm.

Domains of Frailty Predict Loss of Independence in Older Adults After Noncardiac Surgery.

IMPORTANCE: Preoperative frailty has been consistently associated with death, severe complications, and loss of independence (LOI) after surgery. LOI is an important patient-centered outcome, but it is unclear which domains of frailty are most strongly associated with LOI. Such information would be important to target individual geriatric domains for optimization. OBJECTIVE: To assess whether impairment in individual domains of the Edmonton Frail Scale (EFS) can predict LOI in older adults after noncardiac surgery. DESIGN: Retrospective Cohort Study. SETTING: One Academic Hospital. PARTICIPANTS: Patients aged 65 or older who were living independently and evaluated with the EFS during a preoperative visit to the Center for Preoperative Optimization at the Johns Hopkins Hospital between June 2018 and January 2020. MAIN OUTCOME: LOI defined as discharge to increased level of care outside of the home with new mobility deficit or functional dependence. New mobility deficit and functional dependence were extracted from chart review of the standardized occupational therapy and physical therapy assessment performed before discharge. RESULTS: A total of 3497 patients were analyzed. Age (mean±SD) was 73.4±6.2 years, and 1579 (45.2%) were female. The median total EFS score was 3 (range 0-16), and 725/3497 (27%) were considered frail (EFS≥6). The frequencies of impairment in each EFS domain were functional performance (33.5% moderately impaired, 11% severely impaired), history of hospital readmission (42%), poor self-described health status (37%), and abnormal cognition (17.1% moderately impaired, 13.8% severely impaired). Overall, 235/3497 (6.7%) patients experienced LOI. Total EFS score was associated with LOI (odds ratio: 1.37, 95% CI, 1.30-1.45, P <0.001) in a model adjusted for age, sex, body mass index, American Society of Anesthesiologists rating, congestive heart failure, valvular heart disease, hypertension diagnosis, chronic lung disease, diabetes, renal failure, liver disease, weight loss, anemia, and depression. Using a nested log likelihood approach, the domains of functional performance, functional dependence, social support, health status, and urinary incontinence improved the base multivariable model. In cross-validation, total EFS improved the prediction of LOI with the final model achieving an area under the curve of 0.840. Functional performance was the single domain that most improved outcome prediction, but together with functional dependence, social support, and urinary incontinence, the model resulted in an area under the curve of 0.838. CONCLUSION AND RELEVANCE: Among domains measured by the EFS before a wide range of noncardiac surgeries in older adults, functional performance, functional dependence, social support, and urinary incontinence were independently associated with and improved the prediction of LOI. Clinical initiatives to mitigate LOI may consider screening with the EFS and targeting abnormalities within these domains.

Characterizing Tumor Thrombus Arising from Non-Clear Cell Renal Cell Carcinoma.

Background: Renal cell carcinoma (RCC) can exhibit a unique vascular tropism that enables tumor thrombus extension into the inferior vena cava (IVC). While most RCC subtypes that form tumor thrombi are of clear cell (cc) histology, non-clear cell (ncc) subtypes can also exhibit this unique growth pattern. Objective: To characterize clinicopathologic differences and survival outcomes among patients with IVC tumor thrombus arising from ccRCC versus nccRCC. Design setting and participants: Patients diagnosed with IVC tumor thrombus secondary to RCC in our institutional experience from 2003 to 2021 were identified. Outcome measurements and statistical analysis: Clinicopathologic characteristics were compared by histology. Perioperative and oncologic outcomes including recurrence-free (RFS), overall (OS), and cancer-specific (CSS) survival were assessed using multivariable Cox regression analyses. Results and limitations: The analyzed cohort included 103 patients (82 ccRCC and 21 nccRCC). There were no significant differences in baseline demographic parameters. Patients with nccRCC were more likely to have regional lymph node involvement (42.9% vs 20.7%, p = 0.037). No differences in perioperative outcomes, IVC resection, or IVC reconstruction were observed between groups. The median follow-up time was 30 mo. The median RFS was 30 (nccRCC) versus 53 (ccRCC) mo (p = 0.1). There was no significant difference in OS or CSS. This study was limited by its small sample size. Conclusions: Patients with IVC tumor thrombus arising from ccRCC and nccRCC exhibit similar perioperative and oncologic outcomes. While surgical appropriateness was not impacted by histologic subtype, multimodal strategies are needed to improve outcomes for patients with tumor thrombus. Patient summary: Renal cell carcinoma (RCC) can uniquely invade vasculature and form a tumor thrombus. This study examined the difference in outcomes of patients with tumor thrombus based on RCC subtype (clear cell vs non-clear cell). We found that patients exhibited similar surgical and survival outcomes regardless of RCC type.

Association Between Left Ventricular Relative Wall Thickness and Acute Kidney Injury After Noncardiac Surgery.

BACKGROUND: Acute kidney injury (AKI) after major noncardiac surgery is commonly attributed to cardiovascular dysfunction. Identifying novel associations between preoperative cardiovascular markers and kidney injury may guide risk stratification and perioperative intervention. Increased left ventricular relative wall thickness (RWT), routinely measured on echocardiography, is associated with myocardial dysfunction and long-term risk of heart failure in patients with preserved left ventricular ejection fraction (LVEF); however, its relationship to postoperative complications has not been studied. We evaluated the association between preoperative RWT and AKI in high-risk noncardiac surgical patients with preserved LVEF. METHODS: Patients ≥18 years of age having major noncardiac surgery (high-risk elective intra-abdominal or noncardiac intrathoracic surgery) between July 1, 2016, and June 30, 2018, who had transthoracic echocardiography in the previous 12 months were eligible. Patients with preoperative creatinine ≥2 mg/dL or reduced LVEF (<50%) were excluded. The association between RWT and AKI, defined as an increase in serum creatinine by 0.3 mg/dL from baseline within 48 hours or by 50% within 7 days after surgery, was assessed using multivariable logistic regression adjusted for preoperative covariates. An additional model adjusted for intraoperative covariates, which are strongly associated with AKI, especially hypotension. RWT was modeled continuously, associating the change in odds of AKI for each 0.1 increase in RWT. RESULTS: The study included 1041 patients (mean ± standard deviation [SD] age 62 ± 15 years; 59% female). A total of 145 subjects (13.9%) developed AKI within 7 days. For RWT quartiles 1 through 4, respectively, 20 of 262 (7.6%), 40 of 259 (15.4%), 39 of 263 (14.8%), and 46 of 257 (17.9%) developed AKI. Log-odds and proportion with AKI increased across the observed RWT values. After adjusting for confounders (demographics, American Society of Anesthesiologists [ASA] physical status, comorbidities, baseline creatinine, antihypertensive medications, and left ventricular mass index), each RWT increase of 0.1 was associated with an estimated 26% increased odds of developing AKI (odds ratio [OR]; 95% confidence interval [CI]) of 1.26 (1.09-1.46; P = .002). After adjusting for intraoperative covariates (length of surgery, presence of an arterial line, intraoperative hypotension, crystalloid administration, transfusion, and urine output), RWT remained independently associated with the odds of AKI (OR; 95% CI) of 1.28 (1.13-1.47; P = .001). Increased RWT was also independently associated with hospital length of stay and adjusted hazard ratio (HR [95% CI]) of 0.94 (0.89-0.99; P = .018). CONCLUSIONS: Left ventricular RWT is a novel cardiovascular factor associated with AKI within 7 days after high-risk noncardiac surgery among patients with preserved LVEF. Application of this commonly available measurement of risk stratification or perioperative intervention warrants further investigation.

Computationally guided high-throughput design of self-assembling drug nanoparticles.

Nanoformulations of therapeutic drugs are transforming our ability to effectively deliver and treat a myriad of conditions. Often, however, they are complex to produce and exhibit low drug loading, except for nanoparticles formed via co-assembly of drugs and small molecular dyes, which display drug-loading capacities of up to 95%. There is currently no understanding of which of the millions of small-molecule combinations can result in the formation of these nanoparticles. Here we report the integration of machine learning with high-throughput experimentation to enable the rapid and large-scale identification of such nanoformulations. We identified 100 self-assembling drug nanoparticles from 2.1 million pairings, each including one of 788 candidate drugs and one of 2,686 approved excipients. We further characterized two nanoparticles, sorafenib-glycyrrhizin and terbinafine-taurocholic acid both ex vivo and in vivo. We anticipate that our platform can accelerate the development of safer and more efficacious nanoformulations with high drug-loading capacities for a wide range of therapeutics.

Assessing the content validity of patient-reported outcome measures in adult myositis: A report from the OMERACT myositis working group.

OBJECTIVE: To investigate the content validity of several patient-reported outcome measures (PROMs) in patients with idiopathic inflammatory myopathies (IIM). METHODS: Seven individual PROM instruments were selected by the Outcome Measures in Rheumatology (OMERACT) Myositis Working Group relating to the following domains: pain, fatigue, physical function and physical activity. Twenty patients from the Johns Hopkins Myositis Center were selected for one-on-one face-to-face or phone interviews for cognitive interviewing of individual PROMs to assess comprehension and content validity. Additionally, patients were asked if they thought muscle symptoms, an area originally identified in qualitative studies, were encapsulated by the other four domains. RESULTS: The majority of patients (>70%) felt that each of the instruments was clear, easy to read and understand, and could be used for assessment of its domain. Two-thirds (66%) of patients felt that 'muscle symptoms' were captured by the other domains. CONCLUSIONS: We provided evidence to support adequate content validity for several PROMs. Further research is needed to determine whether 'muscle symptoms' warrant a separate domain.

Robotically handled whole-tissue culture system for the screening of oral drug formulations.

Monolayers of cancer-derived cell lines are widely used in the modelling of the gastrointestinal (GI) absorption of drugs and in oral drug development. However, they do not generally predict drug absorption in vivo. Here, we report a robotically handled system that uses large porcine GI tissue explants that are functionally maintained for an extended period in culture for the high-throughput interrogation (several thousand samples per day) of whole segments of the GI tract. The automated culture system provided higher predictability of drug absorption in the human GI tract than a Caco-2 Transwell system (Spearman's correlation coefficients of 0.906 and 0.302, respectively). By using the culture system to analyse the intestinal absorption of 2,930 formulations of the peptide drug oxytocin, we discovered an absorption enhancer that resulted in a 11.3-fold increase in the oral bioavailability of oxytocin in pigs in the absence of cellular disruption of the intestinal tissue. The robotically handled whole-tissue culture system should help advance the development of oral drug formulations and might also be useful for drug screening applications.

Light-degradable hydrogels as dynamic triggers for gastrointestinal applications.

Triggerable materials capable of being degraded by selective stimuli stand to transform our capacity to precisely control biomedical device activity and performance while reducing the need for invasive interventions. Here, we describe the development of a modular and tunable light-triggerable hydrogel system capable of interfacing with implantable devices. We apply these materials to two applications in the gastrointestinal (GI) tract: a bariatric balloon and an esophageal stent. We demonstrate biocompatibility and on-demand triggering of the material in vitro, ex vivo, and in vivo. Moreover, we characterize performance of the system in a porcine large animal model with an accompanying ingestible LED. Light-triggerable hydrogels have the potential to be applied broadly throughout the GI tract and other anatomic areas. By demonstrating the first use of light-degradable hydrogels in vivo, we provide biomedical engineers and clinicians with a previously unavailable, safe, dynamically deliverable, and precise tool to design dynamically actuated implantable devices.