Pharmacological PINK1 activation ameliorates Pathology in Parkinson's Disease models.

PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinson's disease (PD) and Parkinsonism, respectively. We demonstrate that pathological α-synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction, and impairs mitophagy as evidenced by the accumulation of the PINK1 substrate pS65-Ubiquitin (pUb). We discovered MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes its active complex, resulting in increased rates of mitophagy. Treatment with MTK458 mediates clearance of accumulated pUb and α-synuclein pathology in α-synuclein pathology models in vitro and in vivo. Our findings from preclinical PD models suggest that pharmacological activation of PINK1 warrants further clinical evaluation as a therapeutic strategy for disease modification in PD.

Artificial Intelligence Versus Expert Plastic Surgeon: Comparative Study Shows ChatGPT "Wins" Rhinoplasty Consultations: Should We Be Worried?

Introduction: Large language models, such as ChatGPT, hold tremendous promise to bridge gaps in patient education and enhance the decision-making resources available online for patients seeking nasal surgery. Objective: To compare the performance of ChatGPT in answering preoperative and postoperative patient questions related to septorhinoplasty. Methods: Two sets of responses were collected for the questions: one from an expert rhinoplasty surgeon with over two decades of experience, and the other from ChatGPT-3.5. Seven expert rhinoplasty surgeons, blinded to the source of responses, independently assessed the responses using a 5-point Likert scale in four performance areas: empathy, accuracy, completeness, and overall quality. Results: ChatGPT outperformed physician responses in three of the four performance areas, earning significantly higher ratings in accuracy, completeness, and overall quality (p < 0.001). In addition, ChatGPT was overwhelmingly preferred over physician responses (p < 0.001), with evaluators favoring ChatGPT in 80.95% of instances. Conclusions: ChatGPT has demonstrated its remarkable ability to deliver accurate, complete, and high-quality responses to preoperative and postoperative patient questions. Although certain improvements are warranted, this artificial intelligence tool has shown its potential to effectively counsel and educate prospective septorhinoplasty patients at a level comparable with or exceeding that of an expert surgeon.

Human microglia maturation is underpinned by specific gene regulatory networks.

Microglia phenotypes are highly regulated by the brain environment, but the transcriptional networks that specify the maturation of human microglia are poorly understood. Here, we characterized stage-specific transcriptomes and epigenetic landscapes of fetal and postnatal human microglia and acquired corresponding data in induced pluripotent stem cell (iPSC)-derived microglia, in cerebral organoids, and following engraftment into humanized mice. Parallel development of computational approaches that considered transcription factor (TF) co-occurrence and enhancer activity allowed prediction of shared and state-specific gene regulatory networks associated with fetal and postnatal microglia. Additionally, many features of the human fetal-to-postnatal transition were recapitulated in a time-dependent manner following the engraftment of iPSC cells into humanized mice. These data and accompanying computational approaches will facilitate further efforts to elucidate mechanisms by which human microglia acquire stage- and disease-specific phenotypes.

Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients.

Transcription factor programs mediating the immune response to coronavirus disease 2019 (COVID-19) are not fully understood. Capturing active transcription initiation from cis-regulatory elements such as enhancers and promoters by capped small RNA sequencing (csRNA-seq), in contrast to capturing steady-state transcripts by conventional RNA-seq, allows unbiased identification of the underlying transcription factor activity and regulatory pathways. Here, we profile transcription initiation in critically ill COVID-19 patients, identifying transcription factor motifs that correlate with clinical lung injury and disease severity. Unbiased clustering reveals distinct subsets of cis-regulatory elements that delineate the cell type, pathway-specific, and combinatorial transcription factor activity. We find evidence of critical roles of regulatory networks, showing that STAT/BCL6 and E2F/MYB regulatory programs from myeloid cell populations are activated in patients with poor disease outcomes and associated with COVID-19 susceptibility genetic variants. More broadly, we demonstrate how capturing acute, disease-mediated changes in transcription initiation can provide insight into the underlying molecular mechanisms and stratify patient disease severity.

Pharmacological PINK1 activation ameliorates Pathology in Parkinson's Disease models.

PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinson's disease (PD) and Parkinsonism, respectively. We demonstrate that pathological α-synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction and impairs mitophagy, driving accumulation of the PINK1 substrate pS65-Ubiquitin (pUb) in primary neurons and in vivo. We synthesized MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes an active heterocomplex, thereby increasing mitophagy. MTK458 mediates clearance of α-synuclein pathology in PFF seeding models in vitro and in vivo and reduces pUb. We developed an ultrasensitive assay to quantify pUb levels in plasma and observed an increase in pUb in PD subjects that correlates with disease progression, paralleling our observations in PD models. Our combined findings from preclinical PD models and patient biofluids suggest that pharmacological activation of PINK1 is worthy of further study as a therapeutic strategy for disease modification in PD. Highlights: Discovery of a plasma Parkinson's Disease biomarker candidate, pS65-Ubiquitin (pUb)Plasma pUb levels correlate with disease status and progression in PD patients.Identification of a potent, brain penetrant PINK1 activator, MTK458MTK458 selectively activates PINK1 by stimulating dimerization and stabilization of the PINK1/TOM complexMTK458 drives clearance of α-synuclein pathology and normalizes pUb in in vivo Parkinson's models.

Effects of L1 adhesion molecule agonistic mimetics on signal transduction in neuronal functions.

The L1 cell adhesion molecule plays an essential role in neural development and repair. It is not only a 'lock and key' recognition molecule, but an important signal transducer that stimulates regenerative-beneficial cellular functions such as neurite outgrowth, neuronal cell migration, survival, myelination, and synapse formation. Triggering L1 functions after neurotrauma improves functional recovery. In addition, loss-of-function mutations in the L1 gene lead to the L1 syndrome, a rare, X-linked neurodevelopmental disorder with an incidence of approximately 1:30,000 in newborn males. To use L1 for beneficial functions, we screened small compound libraries for L1 agonistic mimetics that trigger L1 functions and improve conditions in animal models of neurotrauma and the L1 syndrome. To understand the mechanisms underlying these functions, it is important to gain a better understanding of L1-dependent cellular signaling that is triggered by the L1 agonistic mimetics. We tested the cell signaling features of L1 agonistic mimetics that contribute to neurite outgrowth and neuronal migration. Our findings indicates that L1 agonistic mimetics trigger the same cell signaling pathways underlying neurite outgrowth, but only the L1 mimetics tacrine, polydatin, trimebutine and honokiol trigger neuronal migration. In contrast, the mimetics crotamiton and duloxetine did not affect neuronal migration, thus limiting their use in increasing neuronal migration, leaving open the question of whether this is a desired or not desired feature in the adult.

Tools for studying human microglia: In vitro and in vivo strategies.

Microglia may only represent 10% of central nervous system (CNS) cells but they perform critical roles in development, homeostasis and neurological disease. Microglia are also environmentally regulated, quickly losing their transcriptomic and epigenetic signature after leaving the CNS. This facet of microglia biology is both fascinating and technically challenging influencing the study of the genetics and function of human microglia in a manner that recapitulates the CNS environment. In this review we provide a comprehensive overview of existing in vitro and in vivo methodology to study human microglia, such as immortalized cells lines, stem cell-derived microglia, cerebral organoids and xenotransplantation. Since there is currently no single method that completely recapitulates all hallmarks of human ex vivo adult homeostatic microglia, we also discuss the advantages and limitations of each existing model as a practical guide for researchers.

Lumbar Level Peripheral Nerve Stimulation for Low Back Pain.

Background: Low back pain affects the lives of millions of people in the United States and the world. Not only does low back pain affect the quality of life for the individual patient, but it also accounts for many emergency department and health care visits. For a subset of patients, conservative measures such as medications and physical therapy, nonsurgical interventions, and surgery are not effective. Peripheral nerve stimulation is an emerging treatment option for patients with chronic low back pain. This case series assesses 6 patients' experiences with lumbar level peripheral nerve stimulation. Case Report: Three male and 3 female patients underwent lumbar level peripheral nerve stimulation as a treatment for chronic low back pain. The average age of the patients was 63.5 years, and they demonstrated an average pain reduction of 64.8%. Conclusion: This series provides evidence that lumbar level peripheral nerve stimulation may be an efficacious treatment for chronic low back pain that is refractory to conservative measures. Large studies are needed to assess the outcomes and durations of improvement associated with this treatment.

Increased Peripheral Blood Neutrophil Activation Phenotypes and Neutrophil Extracellular Trap Formation in Critically Ill Coronavirus Disease 2019 (COVID-19) Patients: A Case Series and Review of the Literature.

BACKGROUND: Increased inflammation has been well defined in coronavirus disease 2019 (COVID-19), while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases, and acute respiratory distress syndrome, a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets. METHODS: Blood was obtained serially from critically ill COVID-19 patients for 11 days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis, and cytokine levels were assessed. Lung tissue was obtained immediately postmortem for immunostaining. PubMed searches for neutrophils, lung, and COVID-19 yielded 10 peer-reviewed research articles in English. RESULTS: Elevations in neutrophil-associated cytokines interleukin 8 (IL-8) and interleukin 6, and general inflammatory cytokines IFN-inducible protien-19, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin 1ß, interleukin 10, and tumor necrosis factor, were identified both at first measurement and across hospitalization (P < .0001). COVID-19 neutrophils had exaggerated oxidative burst (P < .0001), NETosis (P < .0001), and phagocytosis (P < .0001) relative to controls. Increased NETosis correlated with leukocytosis and neutrophilia, and neutrophils and NETs were identified within airways and alveoli in lung parenchyma of 40% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected lungs available for examination (2 of 5). While elevations in IL-8 and absolute neutrophil count correlated with disease severity, plasma IL-8 levels alone correlated with death. CONCLUSIONS: Literature to date demonstrates compelling evidence of increased neutrophils in the circulation and lungs of COVID-19 patients. Importantly, neutrophil quantity and activation correlates with severity of disease. Similarly, our data show that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.

Social Media Guidelines for Young Plastic Surgeons and Plastic Surgery Training Programs.

SUMMARY: Social media are a powerful tool that creates a unique opportunity for the young plastic surgeon and trainee to share content, brand oneself, educate the public, and develop one's own professional voice early. The majority of all plastic surgery programs and particularly those that are highly ranked have social media opportunities for their residents, yet clear rules to guide implementation of social media programming in residency have remained unspecified. These guidelines and pitfalls can be used to inform a productive and professional entry into plastic surgery social media use for the resident and young plastic surgeon. Details regarding specific platform use to maximize exposure are provided. The core principles of patient safety and privacy, authentic photography, plastic surgery education and advocacy, and professionalism inform these guidelines. Pitfalls include establishment of an online physician-patient relationship, engaging in debate by means of online reviews, providing medical entertainment, and engaging in non-plastic surgery politics. Use of these guidelines will allow the young plastic surgeon and trainee to succeed by means of social media platforms in an ethical and professional manner.

Profiling Transcription Initiation in Peripheral Leukocytes Reveals Severity-Associated Cis-Regulatory Elements in Critical COVID-19.

The contribution of transcription factors (TFs) and gene regulatory programs in the immune response to COVID-19 and their relationship to disease outcome is not fully understood. Analysis of genome-wide changes in transcription at both promoter-proximal and distal cis-regulatory DNA elements, collectively termed the 'active cistrome,' offers an unbiased assessment of TF activity identifying key pathways regulated in homeostasis or disease. Here, we profiled the active cistrome from peripheral leukocytes of critically ill COVID-19 patients to identify major regulatory programs and their dynamics during SARS-CoV-2 associated acute respiratory distress syndrome (ARDS). We identified TF motifs that track the severity of COVID- 19 lung injury, disease resolution, and outcome. We used unbiased clustering to reveal distinct cistrome subsets delineating the regulation of pathways, cell types, and the combinatorial activity of TFs. We found critical roles for regulatory networks driven by stimulus and lineage determining TFs, showing that STAT and E2F/MYB regulatory programs targeting myeloid cells are activated in patients with poor disease outcomes and associated with single nucleotide genetic variants implicated in COVID-19 susceptibility. Integration with single-cell RNA-seq found that STAT and E2F/MYB activation converged in specific neutrophils subset found in patients with severe disease. Collectively we demonstrate that cistrome analysis facilitates insight into disease mechanisms and provides an unbiased approach to evaluate global changes in transcription factor activity and stratify patient disease severity.

Safety of a Protective Funnel in Primary Breast Augmentation: A Retrospective Analysis of 380 Multicenter Cases in the United States.

BACKGROUND: Protective funnel devices are commonly used to deliver implants in primary breast augmentation (BA) yet there is a paucity of evidence-based data describing their safety in the literature. OBJECTIVES: The purpose of this study was to assess the safety of protective funnels in primary BA within the first 30 days postoperatively. METHODS: This multicenter, Level 3 study retrospectively reviewed the surgical records of 380 consecutive patients (760 breasts) who underwent primary BA by 9 board-certified plastic surgeons using the iNPLANT Funnel (Proximate Concepts LLC, Allendale, NJ) for implant delivery between November 2019 and December 2020. Data were collected pertaining to demographics, implant information, surgery details, and postoperative complications. RESULTS: The mean patient age was 33 years and 76% of patients had a BMI <25 kg/m2. Of this cohort, 11.4% were smokers, 0.8% had diabetes, and 83% were ASA Class 1. All patients received smooth implants with a median volume of 375 cc. A total of 8 (2.1%) complications were reported, including 3 hematomas (0.79%), 1 seroma (0.26%), and 1 superficial infection (0.26%). No patient required explantation. We identified ASA class, BMI, surgery duration, and implant size as potential risk factors. CONCLUSIONS: The data suggest that the use of protective funnels, such as the iNPLANT Funnel, in primary BA is a safe option when these are utilized according to the manufacturer's Instructions for Use. The use of this device led to a low infection rate (0.26%) and a complication rate of (2.1%) consistent with the average reported in the literature (2%-2.5%).1 Implications for clinical practice are encouraging and future research will include a prospective analysis with a larger case series and potentially a control group.

Deep Learning Algorithm for Automated Cardiac Murmur Detection via a Digital Stethoscope Platform.

Background Clinicians vary markedly in their ability to detect murmurs during cardiac auscultation and identify the underlying pathological features. Deep learning approaches have shown promise in medicine by transforming collected data into clinically significant information. The objective of this research is to assess the performance of a deep learning algorithm to detect murmurs and clinically significant valvular heart disease using recordings from a commercial digital stethoscope platform. Methods and Results Using >34 hours of previously acquired and annotated heart sound recordings, we trained a deep neural network to detect murmurs. To test the algorithm, we enrolled 962 patients in a clinical study and collected recordings at the 4 primary auscultation locations. Ground truth was established using patient echocardiograms and annotations by 3 expert cardiologists. Algorithm performance for detecting murmurs has sensitivity and specificity of 76.3% and 91.4%, respectively. By omitting softer murmurs, those with grade 1 intensity, sensitivity increased to 90.0%. Application of the algorithm at the appropriate anatomic auscultation location detected moderate-to-severe or greater aortic stenosis, with sensitivity of 93.2% and specificity of 86.0%, and moderate-to-severe or greater mitral regurgitation, with sensitivity of 66.2% and specificity of 94.6%. Conclusions The deep learning algorithm's ability to detect murmurs and clinically significant aortic stenosis and mitral regurgitation is comparable to expert cardiologists based on the annotated subset of our database. The findings suggest that such algorithms would have utility as front-line clinical support tools to aid clinicians in screening for cardiac murmurs caused by valvular heart disease. Registration URL: https://clinicaltrials.gov; Unique Identifier: NCT03458806.

Prevention of Umbilical Sagging After Medium Definition Liposuction.

BACKGROUND: The loss of the umbilical vertical axis, causing a horizontal shape deformity after liposuction, is a current aesthetic issue. The use of energy devices, such as LASER and VASER, has been advocated as an option for improving skin retraction, but no data are available on the prevention of umbilical sagging. OBJECTIVES: The authors sought to describe a technique for preventing umbilical deformities after medium definition liposuction employing suction-assisted liposuction. METHODS: Over a period of 31 months, 62 patients underwent medium definition liposuction with direct needle fixation of the umbilical stalk to prevent horizontal umbilical deformities. All patients underwent surgery performed by a single surgeon (G.B.). All patients underwent objective measurements of the umbilical shape before and after the procedure utilizing digital image measurements by Mirror Image software, version 6.0 (Fairfield, NJ). Statistical analysis was performed with IBM SPSS Statistics V26. The mean age of the patients was 28.8 years. The follow-up evaluation was performed 2 weeks and 9 months postoperatively. RESULTS: Over a period of 31 months, 60 patients (96.7%) who underwent abdominal etching liposuction showed maintenance of (n = 9, 14.5%) or improvements in the umbilical shape 9 months postoperatively (n = 51, 82.2%, P < 0.05). Two patients (3.2%) experienced worsening of the umbilical shape after surgery despite suture fixation. CONCLUSIONS: Horizontal shape deformities of the umbilicus after liposuction can be improved by utilizing direct needle fixation of the umbilical stalk. The approach has been shown to be effective, safe, and reproducible for the prevention of umbilical sagging in selected patients.

Data-Driven Insights on the Effects of COVID-19 on Aesthetics: Part I (Passive Analysis).

BACKGROUND: Since COVID-19 was declared to be a worldwide pandemic and US national emergency in March (week 11), it has significantly changed aesthetic plastic surgery. As plastic surgeons now move towards reopening practices, understanding public interest in medical aesthetics will be critical to maximize efforts and resource allocation in procedures and treatments that patients want. OBJECTIVES: In this study, the authors sought to passively query public interest in aesthetics utilizing Google Trends search data. METHODS: Google Trends was utilized to quantify relative search volumes over the past 4 years for a variety of categories: patient-related, surgery-related, injectables, breast procedures, face procedures, and body procedures. Data were deseasonalized and represented graphically. Z-scores of each time-point differing from the expected values were determined utilizing least squares regression. RESULTS: Of the 204 significantly anomalous search term data points in 2020, 172 (84.0%) occurred after week 11 (pandemic/national emergency declaration). Sixty percent of searches in all time-points after week 11 significantly differed, and 25/26 (96.0%) search terms experienced significant changes after week 11. There was decreased interest for 18 terms with variable recovery. Procedural nadirs for decreased search volume troughs occurred between weeks 11 and 14. Six patient-related chief complaints saw increased search interest after COVID-19, with peak interest between weeks 11 and 17. CONCLUSIONS: This is the first study, to the authors' knowledge, to assess real-time, national data about the impact of COVID-19 on public interest in aesthetics.

Data-Driven Insights on the Effects of COVID-19 on Public Interest in Medical Aesthetics: Part II (Active Analysis).

BACKGROUND: The COVID-19 pandemic significantly affected financial and psychosocial factors that influence plastic surgery demand. OBJECTIVES: The authors sought to actively assess public interest changes and the reasons underlying these shifts. METHODS: Using Amazons' Mechanical Turk, we crowdsourced public opinions regarding aesthetic interventions from April 30 to May 3, 2020. The survey assessed prior experience with and interest in 6 aesthetic interventions before and during the pandemic and reasons for changing interest. United States residents aged 18 years and over who passed the attention check were included. RESULTS: We included 704 of 838 total responses. One-half of respondents were female; the median age group was 25 to 34 years. During the pandemic, 21% of respondents had increased and 33% decreased interest in at least one intervention. Non-invasive procedures (7.3%), facial aesthetic surgery (6.6%), and medical-grade skincare (5.9%) elicited the greatest interest increase. Seeing themselves in the mirror more often (43.2%), desire to look better after the crisis (41.8%), and increased time on social media (40.4%) were the top reasons for increased interest. The most common reasons for decreased interest were changing spending priorities (58%), focusing on other health aspects (49.8%), and worrying about infection in medical facilities (46.3%). Almost one-half of respondents considered virtual consultations for interventions of increased interest. CONCLUSIONS: The COVID-19 pandemic significantly affected interest in medical aesthetics. Offering telemedicine and discussing detailed COVID-19 infection control policies with patients will be critical to address patient needs and concerns. These findings can be used to improve patient outreach, advertisement, and counseling as practices focus on reopening.

Mediterranean diet adherence and metabolic syndrome in US adolescents.

The Mediterranean diet (MD) has been found to lower the risk of heart disease, stroke, and diabetes in adults. Little is known about its acceptance and relationship to cardiovascular risk markers in US adolescents. Using data from the National Health and Nutrition Examination Survey, years 2007-2014, we performed a cross-sectional analysis of adherence to the Mediterranean diet among a representative sample of US adolescents (n = 4223), factors that influence adherence, and whether adherence is associated with cardiometabolic risk factors including metabolic syndrome. MD adherence was calculated using the KIDMED scoring system. We found that overall MD adherence was very low among US adolescents, with Mexican American youths having higher adherence compared to other groups. Higher income was associated with greater adherence. There was low intake of key MD foods including olive oil and finfish. The unadjusted prevalence of metabolic syndrome was 6.6%. MD adherence was not associated with metabolic syndrome.

Nut consumption and metabolic syndrome in US adolescents.

OBJECTIVE: To determine whether nut intake is associated with the prevalence of metabolic syndrome in US adolescents. DESIGN: A cross-sectional analysis of data from the National Health and Nutrition Examination Survey (NHANES) years 2003-2012. Anthropometric measurements, blood tests, 24 h diet recalls and demographic data were retrieved for participating adolescents. Metabolic syndrome was defined according to paediatric-modified Adult Treatment Panel III criteria. The exposure was defined as a nut intake ≥5 g/d. SETTING: USA. SUBJECTS: Individuals aged 12-19 years (n 2805). RESULTS: Nut consumption was associated with lower odds for metabolic syndrome (crude OR=0·25; 95 % CI 0·11, 0·55; P≤0·001). This effect was independent of age, sex, race/ethnicity and family income:poverty ratio (adjusted OR=0·27; 95 % CI 0·12, 0·61; P=0·002), and was stable after controlling for nutritional covariates including intake of sugar and total energy consumption (OR=0·36; 95 % CI 0·16, 0·81; P=0·014). CONCLUSION: Nut consumption of ≥5 g/d is independently associated with lower odds for metabolic syndrome in US adolescents.