Ionic Liquid Coating-Driven Nanoparticle Delivery to the Brain: Applications for NeuroHIV.

Delivering cargo to the central nervous system (CNS) remains a pharmacological challenge. For infectious diseases such as HIV, the CNS acts as a latent reservoir that is inadequately managed by systemic antiretrovirals (ARTs). ARTs thus cannot eradicate HIV, and given CNS infection, patients experience neurological deficits collectively referred to as "neuroHIV". Herein, the development of bioinspired ionic liquid-coated nanoparticles (IL-NPs) for in situ hitchhiking on red blood cells (RBCs) is reported, which enables 48% brain delivery of intracarotid arterial- infused cargo. Moreover, IL choline trans-2-hexenoate (CA2HA 1:2) demonstrates preferential accumulation in parenchymal microglia over endothelial cells post-delivery. This study further demonstrates successful loading of abacavir (ABC), an ART that is challenging to encapsulate, into IL-NPs, and verifies retention of antiviral efficacy in vitro. IL-NPs are not cytotoxic to primary human peripheral blood mononuclear cells (PBMCs) and the CA2HA 1:2 coating itself confers notable anti-viremic capacity. In addition, in vitro cell culture assays show markedly increased uptake of IL-NPs into neural cells compared to bare PLGA nanoparticles. This work debuts bioinspired ionic liquids as promising nanoparticle coatings to assist CNS biodistribution and has the potential to revolutionize the delivery of cargos (i.e., drugs, viral vectors) through compartmental barriers such as the blood-brain-barrier (BBB).

Colectomy in patients with liver disease: albumin-bilirubin score accurately predicts outcomes.

BACKGROUND: Patients with liver disease undergoing colectomy have higher rates of complications and mortality. The Albumin-Bilirubin score is a recently developed system, established to predict outcomes after hepatectomy, that accounts for liver dysfunction. METHODS: All patients undergoing colectomy were identified in the 2015-2018 American College of Surgeons National Surgical Quality Improvement Program colectomy-targeted database. Demographics and outcomes were compared between patients with Albumin-Bilirubin Grade 1 vs. 2/3. Multivariable regression was performed for outcomes including colorectal-specific complications. Areas under the receiver operative characteristic curves were calculated to determine accuracy of the Albumin-Bilirubin score. RESULTS: Of 86,273 patients identified, 48% (N = 41,624) were Albumin-Bilirubin Grade 1, 45% (N = 38,370) Grade 2 and 7% (N = 6,279) Grade 3. Patents with Grade 2/3 compared to Grade 1 had significantly increased mortality (7.2% vs. 0.9%, p < 0.001) and serious morbidity (31% vs. 12%, p < 0.001). Colorectal-specific complications including anastomotic leak (3.7% vs. 2.8%, p < 0.001) and prolonged ileus (26% vs. 14%, p < 0.001) were higher in patients with Grade 2/3. Grade 2/3 had increased risk of mortality (odds ratio 3.07, p < 0.001) and serious morbidity (1.78, p < 0.001). Albumin-Bilirubin had excellent accuracy in predicting mortality (area under the curve 0.81, p < 0.001) and serious morbidity (0.70, p < 0.001). CONCLUSION: Albumin-Bilirubin is easily calculated using only serum albumin and total bilirubin values. Grade 2/3 is associated with increased rates of mortality and morbidity following colectomy. Albumin-Bilirubin can be applied to risk-stratify patients prior to colectomy.

Robotic Heller Myotomy for Advancements in Surgical Management of Achalasia.

Achalasia is an esophageal motility disorder. It occurs due to the destruction of nerves in the lower esophageal sphincter (LES), which leads to the failure of the LES to relax. Patients typically complain of dysphagia, chest pain, and regurgitation. They often report drinking liquids with solids intake to help propel food boluses into the stomach. The diagnosis of achalasia is typically confirmed with an esophagogram and a motility study (esophageal manometry). An esophagogram classically shows the bird beak sign with tapering in the distal esophagus. The treatment for achalasia includes both surgical and non-surgical options. Surgical treatment is associated with a lower rate of recurrences, high clinical success rate, and durability of symptom relief. The current gold standard of surgical technique is myotomy, or the dividing of the muscle fibers of the distal esophagus. Surgical myotomy can be accomplished via a laparoscopic or robotic technique; per-oral endoscopic myotomy is a new alternative intervention. Due to the theoretical risk of gastroesophageal reflux following a myotomy, an antireflux procedure is sometimes performed. We reviewed the approach to a robotic heller myotomy for the treatment of achalasia.

Systemic racism and racial inequities in periodontal health: The long journey from upstream determinants to downstream treatment.

Racial disparities in the prevalence of periodontal disease are consistent and persistent. The epidemiology of periodontal disease demonstrates racial inequities: non-Hispanic Black (14.7%), Mexican American (13.4%), and other Hispanic adults (7.8%) experience a higher prevalence of severe periodontal disease than non-Hispanic White adults (5.9%). Epidemiologic and clinical research on periodontal health suffers from the same problem that has plagued the health equity movement, an over emphasis on describing racial inequities coupled with few interventions that reduce racial health inequity. Over the decades that racial inequities in periodontal disease have been observed, many have argued that systemic racism is the fundamental driver of racial health inequity. This paper interrogates the roles of systemic racism, dental education, clinical treatment, and patient behavior in periodontal disease. We describe how, together, these mechanisms contribute to racial disparities in periodontal outcomes. However, it is insufficient for oral health equity scientists to only describe and discuss the negative effects of systemic racism. The imperative is to create antiracist strategies designed to eliminate systemic racism. Health equity scientists must also specify how dental systems operate in a racist manner and create effective clinical strategies designed to reduce racial disparities in periodontal disease.

NIR-II emissive donor-acceptor-donor fluorophores for dual fluorescence bioimaging and photothermal therapy applications.

Fluorescence bioimaging with near-infrared II (NIR-II) emissive organic fluorophores has proven to be a viable noninvasive diagnostic technique. However, there is still the need for the development of fluorophores that possess increased stability as well as functionalities that impart stimuli responsiveness. Through strategic design, we can synthesize fluorophores that possess not only NIR-II optical profiles but also pH-sensitivity and the ability to generate heat upon irradiation. In this work, we employ a donor-acceptor-donor (D-A-D) design to synthesize a series of NIR-II fluorophores. Here we use thienothiadiazole (TTD) as the acceptor, 3-hexylthiophene (HexT) as the π-spacer and vary the alkyl amine donor units: N,N-dimethylaniline (DMA), phenylpiperidine (Pip), and phenylmorpholine (Morp). Spectroscopic analysis shows that all three derivatives exhibit emission in the NIR-II region with λemimax ranging from 1030 to 1075 nm. Upon irradiation, the fluorophores exhibited noticeable heat generation through non-radiative processes. The ability to generate heat indicates that these fluorophores will act as theranostic (combination therapeutic and diagnostic) agents in which simultaneous visualization and treatment can be performed. Additionally, biosensing capabilities were supported by changes in the absorbance properties while under acidic conditions as a result of protonation of the alkyl amine donor units. The fluorophores also show minimal toxicity in a human mammary cell line and with murine red blood cells. Overall, initial results indicate viable NIR-II materials for multiple biomedical applications.

To report hounsfeld units or not: There is no question.

INTRODUCTION: Most adrenal incidentalomas are not appropriately evaluated. Reporting the mass in the radiology report summary and providing recommendations in the report can positively impact evaluation. This study evaluated the effect of reporting Hounsfield units(HU) on adrenal incidentaloma follow-up. METHODS: Patients with adrenal incidentalomas identified on noncontrast CT scan from 2015 to 2020 â€‹at a tertiary care institution were studied. Chart review was conducted. Patient and imaging characteristics were compared between patients who did and did not have HU reported. Outcomes of interest were 1)outpatient referral, 2)biochemical evaluation, and 3)dedicated imaging if appropriate. Multivariate analysis determined the impact of HU, reporting in the summary and provision of recommendations on the outcomes. RESULTS: 363 patients were studied, 36(9.9 â€‹%) had HU reported. When HU were used in addition to recommendations and reporting in the summary, the likelihood of outpatient referral increased from 10.1 to 32.6-fold (95%CI 7.7-138.1, p â€‹< â€‹0.001). Similarly, the likelihood of biochemical workup increased from 2.5 to 7.8-fold (95%CI 2.5-24.1, p â€‹< â€‹0.001). CONCLUSION: Recording adrenal incidentaloma HU on non-contrast CT scans was associated with increased rates of outpatient referral and biochemical workup.

Selective Blood Cell Hitchhiking in Whole Blood with Ionic Liquid-Coated PLGA Nanoparticles to Redirect Biodistribution After Intravenous Injection.

Less than 5% of intravenously-injected nanoparticles (NPs) reach destined sites in the body due to opsonization and immune-based clearance in vascular circulation. By hitchhiking in situ onto specific blood components post-injection, NPs can selectively target tissue sites for unprecedentedly high drug delivery rates. Choline carboxylate ionic liquids (ILs) are biocompatible liquid salts <100X composed of bulky asymmetric cations and anions. This class of ILs has been previously shown to significantly extend circulation time and redirect biodistribution in BALB/c mice post-IV injection via hitchhiking on red blood cell (RBC) membranes. Herein, we synthesized & screened 60 choline carboxylic acid-based ILs to coat PLGA NPs and present the impact of structurally engineering the coordinated anion identity to selectively interface and hitchhike lymphocytes, monocytes, granulocytes, platelets, and RBCs in whole mouse blood for in situ targeted drug delivery. Furthermore, we find this nanoparticle platform to be biocompatible (non-cytotoxic), translate to human whole blood by resisting serum uptake and maintaining modest hitchhiking, and also significantly extend circulation retention over 24 hours in BALB/c healthy adult mice after IV injection. Because of their altered circulation profiles, we additionally observe dramatically different organ accumulation profiles compared to bare PLGA NPs. This study establishes an initial breakthrough platform for a modular and transformative targeting technology to hitchhike onto blood components with high efficacy and safety in the bloodstream post-IV administration.

Multi-regional alterations in glucose and purine metabolic pathways in the Parkinson's disease dementia brain.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases, most commonly characterised by motor dysfunction, but also with a high prevalence of cognitive decline in the decades following diagnosis-a condition known as Parkinson's disease dementia (PDD). Although several metabolic disruptions have been identified in PD, there has yet to be a multi-regional analysis of multiple metabolites conducted in PDD brains. This discovery study attempts to address this gap in knowledge. A semi-targeted liquid chromatography-mass spectrometry analysis of nine neuropathologically-confirmed PDD cases vs nine controls was performed, looking at nine different brain regions, including the cingulate gyrus, cerebellum, hippocampus, motor cortex, medulla, middle temporal gyrus, pons, substantia nigra and primary visual cortex. Case-control differences were determined by multiple t-tests followed by 10% FDR correction. Of 64 identified analytes, 49 were found to be altered in at least one region of the PDD brain. These included metabolites from several pathways, including glucose and purine metabolism and the TCA cycle, with widespread increases in fructose, inosine and ribose-5-phosphate, as well as decreases in proline, serine and deoxyguanosine. Higher numbers of alterations were observed in PDD brain regions that are affected during earlier α-synuclein Braak stages-with the exception of the cerebellum, which showed an unexpectedly high number of metabolic changes. PDD brains show multi-regional alterations in glucose and purine metabolic pathways that reflect the progression of α-synuclein Braak staging. Unexpectedly, the cerebellum also shows a high number of metabolic changes.

Pain Control after Reduction Mammaplasty with Combination Bupivacaine and Dexamethasone Regional Block: A Randomized Controlled Trial.

BACKGROUND: There are many approaches to pain control in reduction mammaplasty. Preoperative bupivacaine regional blocks control pain relatively inexpensively ($0.07/mL), but last only 8 hours. A liposomal bupivacaine formulation lasts 72 hours but can be costly ($17.21/mL). Orthopedic and thoracic operations have demonstrated that dexamethasone ($0.44/mL) plus bupivacaine can prolong analgesia. The authors conducted a double-blind, randomized, controlled trial to determine whether dexamethasone plus bupivacaine regional block improves postoperative pain control, reduces inpatient narcotic use, and improves patient satisfaction. METHODS: Female patients were randomized into control and experimental groups. Both groups received preoperative modified block of the pectoral nerves: bupivacaine plus saline (control group) or bupivacaine plus dexamethasone (experimental group). Postoperative pain regimens were standardized. Vital signs, pain scores, narcotic consumption, and antiemetic use were recorded throughout the hospitalization. Quality-of-life surveys were distributed at the first postoperative visit. RESULTS: Fifty-one patients completed the study: 25 control and 26 experimental group patients. The experimental group averaged lower pain scores, although there was no statistically significant difference overall or at each 4-hour interval. Postoperative narcotic use was significantly lower in the experimental group (mean, 23.2 oral morphine equivalents versus 36.6 oral morphine equivalents per patient; P = 0.026). There were no differences in 4-hour interval vital signs, antiemetic use, or length of stay. Survey results showed enhanced quality of life in the experimental group, but this was not statistically significant. CONCLUSIONS: The addition of dexamethasone to bupivacaine in the preoperative modified block of the pectoral nerves block before bilateral reduction mammaplasty resulted in significantly less narcotic consumption in the hospital. This can be a cost-effective adjunct for postoperative pain control. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Changes in dental and medical visits before and during the COVID-19 pandemic among U.S. children aged 1-17 years.

OBJECTIVES: The COVID-19 pandemic has tremendously impacted the U.S. healthcare system, but no study has examined the impact of the pandemic on utilization of dental care among U.S. children. Changes in past-year dental versus medical visits and perceived unmet health needs between 2019 and 2020 among U.S. children aged 1-17 years were examined. METHODS: National and state representative, cross-sectional data from the National Survey of Children's Health conducted during June 2019-January 2020 (i.e. pre-pandemic, n = 28 500) and July 2020-January 2021 (i.e. intra-pandemic, n = 41 380) were analysed. Any past-year visit and perceived unmet needs (i.e. delay or inability to receive needed care) were reported by the parent proxy. Weighted prevalence estimates were compared using two-tailed chi-squared tests at p < .05. Poisson regression analyses were used to explore the relationship between having dental and/or medical unmet needs during the pandemic and indicators of poor health and social wellbeing. RESULTS: Between 2019 and 2020, a significantly reduced prevalence of past-year medical (87.2%-81.3%) and dental visits (82.6%-78.2%) among U.S. children aged 1-17 years (all p < .05) were observed. Correspondingly, perceived unmet needs increased by half for dental care (from 2.9% in 2019 to 4.4% in 2020) and almost one-third for medical care (from 3.2% to 4.2% in 2020). Subgroups with the highest prevalence of unmet dental need included those with low socio-economic status, living with their grandparents, uninsured and living with a smoker. CONCLUSIONS: Unmet health needs increased in general but increased more for dental than for medical care among U.S. children aged 1-17 years. Enhanced and sustained efforts will be needed to deliver targeted services towards disadvantaged segments of the population to narrow existing disparities.

Slipping through the cracks: Just how underrepresented are minorities within the dental specialties?

OBJECTIVE: There is a lack of diversity in the dental workforce. Efforts to enhance underrepresented minority (URM) recruitment and retention within dental school exist, but little effort has been made to track URM providers through education and practice. This study assesses the status of workforce diversity in the dental specialties and the predictors of URM dentist specialization. METHODS: The primary data used were a 2012 national sample survey of Hispanic/Latino (H/L), Black, or American Indian/Alaska Native (AI/AN) dentists in the US, supplemented by publicly available workforce data. Descriptive and multivariate statistical analyses were performed to describe the demographic composition of URM clinical general and specialist dentists and analyze changes in proportions of URMs specializing among age cohorts, differences in specific type of specialization, and racial concordance between specialists and their patients. RESULTS: The pathway continues to winnow with fewer URM dentists in specialty practice. Among all URM clinical dentists being first in his/her family to obtain a college degree, having a strong desire to work in his/her own cultural community or joining a loan repayment program due to debt load independently predicted lower odds of specialization. Alternatively, being initially foreign trained as a dentist and valuing professional training were independently predictive of higher odds of specialization. CONCLUSION: The lack of diversity within the dental specialties is a critical flaw in our education and care delivery systems demanding clear actions toward improving the pathway into residency programs for URM students.

Incisional Negative Pressure Wound Therapy Is Protective Against Postoperative Cardiothoracic Wound Infection.

BACKGROUND: Sternal wound infections are a rare but life-threatening complication of cardiothoracic surgery. Prior literature has supported the use of negative pressure wound therapy to decrease sternal wound infections and promote healing. This study sought to determine whether closed incision negative pressure therapy reduced wound infection and improved outcomes in cardiothoracic surgery. METHODS: A retrospective cohort study was performed including all adult patients who underwent nontraumatic cardiothoracic surgery at a single institution between 2016 and 2018 (n = 1199). Patient characteristics, clinical variables, and surgical outcomes were compared between those who did and did not receive incisional negative pressure wound therapy intraoperatively. Multivariable logistic regression analysis determined factors predictive or protective of the development of complications. RESULTS: Incisional negative pressure wound therapy was used in 58.9% of patients. Patients who received this therapy were older with statistically higher rates of hyperlipidemia, statin, and antihypertensive use. The use of negative pressure wound therapy was found to significantly reduce rates of both wound infection (3.0% vs 6.3%, P = 0.01) and readmission for wound infection (0.7% vs 2.6%, P = 0.01). After controlling for confounding variables, negative pressure wound therapy was found to be a protective factor of surgical wound infection (odds ratio, 0.497; 95% confidence interval, 0.262-0.945). CONCLUSIONS: In the largest population studied to date, this study supported the expanded use of negative pressure therapy on sternal wound incisions to decrease infection rates.

Excess S-adenosylmethionine inhibits methylation via catabolism to adenine.

The global dietary supplement market is valued at over USD 100 billion. One popular dietary supplement, S-adenosylmethionine, is marketed to improve joints, liver health and emotional well-being in the US since 1999, and has been a prescription drug in Europe to treat depression and arthritis since 1975, but recent studies questioned its efficacy. In our body, S-adenosylmethionine is critical for the methylation of nucleic acids, proteins and many other targets. The marketing of SAM implies that more S-adenosylmethionine is better since it would stimulate methylations and improve health. Previously, we have shown that methylation reactions regulate biological rhythms in many organisms. Here, using biological rhythms to assess the effects of exogenous S-adenosylmethionine, we reveal that excess S-adenosylmethionine disrupts rhythms and, rather than promoting methylation, is catabolized to adenine and methylthioadenosine, toxic methylation inhibitors. These findings further our understanding of methyl metabolism and question the safety of S-adenosylmethionine as a supplement.

Predicting Outcomes in Thyroidectomy and Parathyroidectomy: The Modified Five-Point Frailty Index Versus American Society of Anesthesiologists Classification.

INTRODUCTION: Thyroidectomy and parathyroidectomy are relatively safe procedures, with overall morbidity rates of 2%-5%. The increasing age is associated with higher likelihood of poor outcomes. The modified five-point frailty index (mFI-5) is associated with complications, but many surgeons are unfamiliar with mFI-5. We assessed the accuracy of the mFI-5 versus the commonly-used American Society of Anesthesiologists (ASA) classification to predict complications following thyroidectomy and parathyroidectomy. METHODS: Patients undergoing thyroidectomy or parathyroidectomy in 2015-2018 NSQIP datasets were identified. The mFI-5 scores were calculated by adding the number of the following comorbidities: congestive heart failure, hypertension requiring medication, chronic obstructive pulmonary disease, diabetes, and nonindependent functional status. Receiver operating characteristics curves were plotted for 30-d mortality and serious morbidity (defined as deep surgical site infection, dehiscence, unplanned intubation, failure to wean from the ventilator 48-h postoperatively, acute renal failure, pneumonia, pulmonary embolism, myocardial infarction, cardiac arrest requiring cardiopulmonary resuscitation, sepsis, septic shock, cerebrovascular accident, or reoperation) using mFI-5 and ASA classification. Areas under these curves (AUC) were compared. RESULTS: Ninety-two thousand, six hundred and ninety-one patients were studied. The mFI-5 and ASA were fair predictors of 30-d mortality (AUC 0.75 and 0.82, respectively) and good predictors of serious morbidity (AUC 0.61 and 0.64). After stratification by age, ASA was superior to mFI-5 in predicting mortality for patients aged 65, 70, 80 y, and older, for the entire population and for thyroidectomy and parathyroidectomy separately. CONCLUSIONS: The ASA classification is a better predictor of mortality and serious morbidity than mFI-5 among patients undergoing thyroidectomy or parathyroidectomy and may be a better prognostic indicator to use when counseling patients before low-risk neck surgery.