Systemic inflammation and acute kidney injury after colorectal surgery.

BACKGROUND: In this retrospective review, the relative importance of systemic inflammation among other causes of acute kidney injury (AKI) was investigated in 1224 consecutive colorectal surgery patients. A potential benefit from reducing excessive postoperative inflammation on AKI might then be estimated. METHODS: AKI was determined using the Kidney Disease Improving Global Outcomes (KDIGO) criteria. The entire population (mixed group), composed of patients with or without sepsis, and a subpopulation of patients without sepsis (aseptic group) were examined. Markers indicative of inflammation were procedure duration, the first postoperative white blood cell (POD # 1 WBC) for the mixed population, and the neutrophil-to-lymphocyte ratio (POD #1 NLR) for the aseptic population. Multivariable logistic regression was then performed using significant (P < 0.05) predictors. The importance of inflammation among independent predictors of AKI and AKI-related complications was then assessed. RESULTS: AKI occurred in 24.6% of the total population. For the mixed population, there was a link between inflammation (POD # 1 WBC) and AKI (P = 0.0001), on univariate regression. Medications with anti-inflammatory properties reduced AKI: ketorolac (P = 0.047) and steroids (P = 0.038). Similarly, in an aseptic population, inflammation (POD # 1 NLR) contributed significantly to AKI (P = 0.000). On multivariable analysis for the mixed and aseptic population, the POD #1 WBC and the POD #1 NLR were independently associated with AKI (P = 0.000, P = 0.022), as was procedure duration (P < 0.0001, P < 0.0001). Inflammation-related parameters were the most significant contributors to AKI. AKI correlated with complications: postoperative infections (P = 0.016), chronic renal insufficiency (CRI, P < 0.0001), non-infectious complications (P = 0.010), 30-day readmissions (P = 0.001), and length of stay (LOS, P < 0.0001). Inflammation, in patients with or without sepsis, was similarly a predictor of complications: postoperative infections (P = 0.002, P = 0.008), in-hospital complications (P = 0.000, P = 0.002), 30-day readmissions (P = 0.012, P = 0.371), and LOS (P < 0.0001, P = 0.006), respectively. CONCLUSIONS: Systemic inflammation is an important cause of AKI. Limiting early postsurgical inflammation has the potential to improve postoperative outcomes.

Altered sleep architecture in children and adolescents with Down syndrome.

OBJECTIVE: Children with Down syndrome (DS) may experience changes in sleep architecture (i.e., different sleep stages) that then affect waketime functioning, including learning, mood, and disruptive behavior. For designing and testing interventions, it is important to document any differences in sleep architecture in children with DS with and without co-occurring diagnoses, including neuropsychiatric diagnoses and obstructive sleep apnea (OSA). METHODS: A retrospective cohort study was performed at Massachusetts General Hospital for children and adolescents with DS who underwent polysomnography (PSG) between August 2016 and July 2022. Patient data collected from the electronic medical record included diagnoses, age at PSG, and PSG report. Statistical analysis included unpaired T tests to test hypotheses about differences in sleep architecture within age groups, and differences between children with DS and a co-occurring diagnosis. One way ANOVA was used to determine statistical significance of OSA severity within patients with DS. RESULTS: When compared by age group, those with DS had negative changes in sleep architecture (e.g., less sleep and more wake) when compared to normative data. Within this cohort, having a co-occurring diagnosis of autism resulted in further, negative effects on sleep architecture. 89% of those with DS had diagnosed OSA but only those with severe OSA experienced negative effects on sleep architecture. CONCLUSION: Age is an important covariate when studying the sleep of children with DS and neurotypical children. Studies are needed to test whether minimizing the observed differences in sleep architecture will translate to improved learning, mood, and behavioral outcomes, and how treating OSA affects sleep architecture.

Treatment of Severe Hyperglycemia in Patients Without Diabetes After Colorectal Surgery.

Background: Several studies have suggested that intravenous insulin therapy for post-operative hyperglycemia improves outcomes after colorectal surgery. Despite the potential benefit, there is a reluctance to use this approach in patients without diabetes mellitus because of an unproven benefit and the potential for hypoglycemia. In this study, we examined whether sliding-scale insulin is sufficient to improve outcomes or if stricter glucose control is necessary. Patients and Methods: Of 1,064 consecutive colorectal surgery patients between August 2016 and December 2021, 478 patients without diabetes mellitus had an average of 6.4 ± 3.1 glucose samples taken within 48 hours after surgery. Sixty-six percent of patients with severe hyperglycemia (glucose ≥180 mg/dL) received sliding-scale insulin. Complication rates and effects of insulin were examined. Results: Severe hyperglycemia was associated with a higher total infection rate (p < 0.002), National Healthcare Safety Network-reported infections (NHSN; p < 0.026), total complications (p < 0.001), and length of stay (LOS; p < 0.000). Sliding-scale insulin did not lower the risk of infection or other complications. Hypoglycemia (glucose <70 mg/dL) occurred in 3.5% of patients, but was not related to insulin use, and was predictable with clinical variables: albumin (p < 0.032), operative duration (p < 0.012), and average post-operative glucose (p < 0.002; area under the curve [AUC], 0.86). Conclusions: Our data confirm that severe post-operative hyperglycemia in patients without diabetes mellitus after colorectal surgery is associated with complications. Sliding-scale insulin was safe but not effective. Treatment before severe hyperglycemia is reached, not after its occurrence, may be beneficial.

Postoperative Hyperglycemia in Patients with and without Diabetes After Major Joint Replacement: The Impact of an Enhanced Glucose Management Program.

BACKGROUND: Perioperative hyperglycemia can have an even more detrimental effect on postoperative outcomes in patients without diabetes than in patients with diabetes, but it has not been established if the treatment of patients without diabetes is safe and effective. We hypothesized that sliding-scale insulin for severe postoperative hyperglycemia (glucose ≥180 mg/dL) could lower mean postoperative glucose levels and minimize short-term complications in patients without diabetes undergoing major joint replacement. METHODS: In a prospective study group, 1,398 consecutive patients, with and without diabetes, undergoing joint replacement were monitored and treated for hyperglycemia and were compared with 886 historical, less frequently monitored controls. The primary outcome was the mean glucose level in patients with and without diabetes within 48 hours after the surgical procedure. Two secondary outcomes could be examined only in the prospective study group, which, by design, had much more frequent glucose sampling and insulin use than the historical controls. First, the contribution of comorbidities and procedural factors to postoperative hyperglycemia in patients without diabetes was assessed with multivariable linear regression. Second, the ability of insulin treatment to reduce complications in patients without diabetes who developed hyperglycemia was evaluated. RESULTS: In comparison with 886 historical controls, enhanced glucose management lowered the mean glucose (and standard deviation) from 129 ± 28 mg/dL to 123 ± 23 mg/dL for patients without diabetes (p = 0.041). Multivariable linear regression revealed factors that contributed to elevated mean glucose in patients without diabetes: preoperative fasting glucose (p < 0.001), perioperative steroid use (p < 0.001), general anesthesia (p < 0.001), procedure duration (p = 0.003), and transfusion (p 0.008). Of 968 patients without diabetes, 203 developed severe hyperglycemia. The recommended insulin coverage was given to 129 of these patients, and 74 patients did not receive it for various clinical reasons. Insulin treatment reduced the frequency of positive cultures from any site (p = 0.025) and a composite of positive cultures and readmissions (p = 0.006) in comparison with no insulin treatment. No patient without diabetes who received insulin experienced mild or severe hypoglycemia. CONCLUSIONS: Postoperative hyperglycemia is frequent in patients without diabetes after orthopaedic surgery, but an enhanced glucose management program can lower mean postoperative glucose levels. The treatment of hyperglycemia in patients without diabetes reduced short-term complications and was associated with minimal side effects. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Single-cell protein expression of hiPSC-derived cardiomyocytes using Single-Cell Westerns.

The ability to reprogram human somatic cells into human induced pluripotent stem cells (hiPSCs) has enabled researchers to generate cell types in vitro that have the potential to faithfully recapitulate patient-specific disease processes and phenotypes. hiPSC-derived cardiomyocytes (hiPSC-CMs) offer the promise of in vitro patient- and disease-specific models for drug testing and the discovery of novel therapeutic approaches for treating cardiovascular diseases. While methods to differentiate hiPSCs into cardiomyocytes have been demonstrated, the heterogeneity and immaturity of these differentiated populations have restricted their potential in reproducing human disease and the associated target cell phenotypes. These barriers may be overcome through comprehensive single-cell characterization to dissect the rich heterogeneity of hiPSC-CMs and to study the source of varying cell fates. In this study, we optimized and validated a new Single-Cell Western method to assess protein expression in hiPSC-CMs. To better understand distinct subpopulations generated from cardiomyocyte differentiations and to track populations at single-cell resolution over time, we measured and quantified the expression of cardiomyocyte subtype-specific proteins (MLC2V and MLC2A) using Single-Cell Westerns. By understanding their heterogeneity through single-cell protein expression and quantification, we may improve upon current cardiomyocyte differentiation protocols, generate hiPSC-CMs that are more representative of in vivo derived cardiomyocytes for disease modeling, and utilize hiPSC-CMs for regenerative medicine purposes. Single-Cell Westerns provide a robust platform for protein expression analysis at single-cell resolution.

Controversy About Withdrawal of Postresuscitation Care After Cardiac Arrest.

With increasing focus in the last decade on post-cardiac arrest care in pediatrics, return of spontaneous circulation, survival rates, and neurologic outcome have improved. As part of this postarrest care, both the American Heart Association and the American Academy of Neurology state it is reasonable to consider targeted temperature management in pediatric comatose patients, although this care is challenging and time sensitive, with many gaps in knowledge remaining. Many pediatric patients will still not survive or will suffer severe neurocognitive impairment despite the therapeutic arsenal provided. Adult guidelines suggest providing postarrest supportive care and limiting prognosis discussions with families until after 72 hours of therapy, but pediatric clinicians are advised to consider a multitude of factors given the lack of data. What, then, should clinicians do if family members of a patient who has been resuscitated request the withdrawal of all life support in the 24 hours immediately postarrest? In this Ethics Rounds, we present such a case and the responses of different clinicians and bioethicists.

High-Dose Inhaled Nitric Oxide as Adjunct Therapy in Cystic Fibrosis Targeting Burkholderia multivorans.

BACKGROUND: Individuals with cystic fibrosis (CF) have persistent lung infections, necessitating the frequent use of antibiotics for pulmonary exacerbations. Some respiratory pathogens have intrinsic resistance to the currently available antibiotics, and any pathogen may acquire resistance over time, posing a challenge to CF care. Gaseous nitric oxide has been shown to have antimicrobial activity against a wide variety of microorganisms, including common CF pathogens, and offers a potential inhaled antimicrobial therapy. Case Presentation. Here, we present the case of a 16-year-old female with CF who experienced a precipitous decline in lung function over the prior year in conjunction with worsening antibiotic resistance of her primary pathogen, Burkholderia multivorans. She received 46 intermittent inhalations of 160 parts-per-million nitric oxide over a 28-day period. The gas was administered via a mechanical ventilator fitted with nitrogen dioxide scavenging chambers. CONCLUSIONS: High-dose inhaled nitric oxide was safe, well tolerated, and showed clinical benefit in an adolescent with cystic fibrosis and pulmonary colonization with Burkholderia multivorans.

Antipsychotics and oropharyngeal dysphagia in hospitalized older patients.

In the inpatient setting, dysphagia is a common, morbid, and costly condition. Antipsychotic medications in older patients have been associated with dysphagia. The purpose of this study was to determine if hospitalized patients who were exposed to antipsychotic medications had worse swallowing function than those who were not exposed. Retrospectively, all patients referred for swallowing difficulty who underwent a videofluoroscopic swallowing study during the course of their hospital care were considered eligible. We excluded patients younger than 50 years and those with a history of dysphagia, a medical cause for dysphagia, or chronic antipsychotic medication usage. Patients exposed to antipsychotics (n = 17) were matched at a 3:1 ratio to patients without exposure (n = 51) for age, comorbidity, and anticholinergic risk. Videofluoroscopic swallowing study was scored according to the Dysphagia Severity Rating Scale (range, 0-6; 6 = worst). Patients who were given antipsychotic medications scored significantly worse on the Dysphagia Severity Rating Scale compared with matched controls (4.1 +/- 1.0 vs 3.0 +/- 1.4; P < 0.01). Using the medication and dosage, the antipsychotic exposure was quantified by converting to chlorpromazine equivalency units. Higher doses of antipsychotic medication were associated with worse swallowing function (P = 0.04). Thus, the potential impact on swallow functions should be considered when prescribing antipsychotic medications in older patients.

Hrt and Hes negatively regulate Notch signaling through interactions with RBP-Jkappa.

Notch signaling is central to cell differentiation, organ development, and apoptosis. Upon ligand binding, the Notch intracellular domain (NotchIC) translocates to the nucleus to interact with its DNA-binding partner, RBP-Jkappa. The NotchIC-RBP-Jkappa complex activates target genes, such as those encoding the Hrt and Hes families of basic-helix-loop-helix (bHLH) transcriptional repressors. Hrt transcripts are enriched in the developing cardiovascular system, and mice lacking Hrt2 have cardiac malformations. Here we show that Hrt2 and Hes1 interact with RBP-Jkappa to negatively regulate Notch-dependent activation of Hrt and Hes expression. The bHLH domain of Hrt2 was necessary for this interaction, and disrupting the protein complex abrogated the negative autoregulation. The interaction did not interfere with the formation or DNA-binding of the NotchIC-RBP-Jkappa complex, indicating direct inhibition by Hrt and Hes as co-repressors. These findings suggest a novel mechanism for negative feedback on Notch signaling that requires RBP-Jkappa to interact physically with Hrt and Hes.

Hairy-related transcription factors inhibit GATA-dependent cardiac gene expression through a signal-responsive mechanism.

Combinatorial actions of transcription factors in multiprotein complexes dictate gene expression profiles in cardiac development and disease. The Hairy-related transcription factor (HRT) family of basic helix-loop-helix proteins is composed of transcriptional repressors highly expressed in the cardiovascular system. However, it has remained unclear whether HRT proteins modulate gene expression driven by cardiac transcriptional activators. Here, we have shown that HRT proteins inhibit cardiac gene transcription by interfering with GATA transcription factors that are implicated in cardiac development and hypertrophy. HRT proteins inhibited GATA-dependent transcriptional activation of cardiac gene promoters such as the atrial natriuretic factor (ANF) promoter. Adenovirus-mediated expression of Hrt2 suppressed mRNA expression of ANF and other cardiac-specific genes in cultured cardiomyocytes. Among various signaling molecules implicated in cardiomyocyte growth, constitutively active Akt1/protein kinase B alpha relieved Hrt2-mediated inhibition of GATA-dependent transcription. HRT proteins physically interacted with GATA proteins, and the basic domain of HRT was critical for physical association as well as transcriptional inhibition. These results suggest that HRT proteins may regulate specific sets of cardiac genes by modulating the function of GATA proteins and other cardiac transcriptional activators in a signal-dependent manner.

The budding yeast silencing protein Sir1 is a functional component of centromeric chromatin.

In fission yeast and multicellular organisms, centromere-proximal regions of chromosomes are heterochromatic, containing proteins that silence gene expression. In contrast, the relationship between heterochromatin proteins and kinetochore function in the budding yeast Saccharomyces cerevisiae remains largely unexplored. Here we report that the yeast heterochromatin protein Sir1 is a component of centromeric chromatin and contributes to mitotic chromosome stability. Sir1 recruitment to centromeres occurred through a novel mechanism independent of its interaction with the origin recognition complex (ORC). Sir1 function at centromeres was distinct from its role in forming heterochromatin, because the Sir2-4 proteins were not associated with centromeric regions. Sir1 bound to Cac1, a subunit of chromatin assembly factor I (CAF-I), and helped to retain Cac1 at centromeric loci. These studies reveal that although budding yeast and mammalian cells use fundamentally different mechanisms of forming heterochromatin, they both use silencing proteins to attract the histone deposition factor CAF-I to centromeric chromatin.