Comparison of Patterns and Demographics of Isolated Traumatic Mandibular Fracture Between Incarcerated and General Populations.

Introduction The management of maxillofacial trauma can be challenging in different unique clinical presentations. While maxillofacial fractures vary in location based on the mechanism of injury, the mandibular fracture is noted to be one of the most common facial fractures. The objective of this study was to explore the differences in injury patterns, outcomes, and demographics of isolated traumatic mandibular fractures between incarcerated and general populations. Methods This retrospective study analyzed consecutive patients presenting for trauma care from January 1, 2010, to December 31, 2020, at the Arrowhead Regional Medical Center (ARMC). Patients 18 years and older were included in this study. Patients diagnosed with mandibular fracture as the primary diagnosis at admission and discharge were identified using the International Classification of Disease, Ninth and Tenth Revision (ICD-9, ICD-10) Code. Patient demographics were extracted from their electronic medical records and included race, marital status, and insurance status. Results A total of 1080 patients with confirmed mandibular fractures were included in the final analysis. Among these patients, 87.5% (n=945) were males, 40% (n=432) of the patients were Hispanic, and the average age was 31.55 years old. The most common mechanism of injury was blunt trauma secondary to assault. Compared to the general population with mandibular fracture, the incarcerated patients with mandibular fracture were more likely to be males (96.1% vs 86.1% for incarcerated population vs. general population respectively, p=0.0005). No other variables were statistically different between these two groups. Conclusion The evidence from this study suggests that the patterns, outcomes, and demographics of mandibular fracture in both incarcerated and general populations are similar.

Cellular therapeutics and immunotherapies in wound healing - on the pulse of time?

Chronic, non-healing wounds represent a significant challenge for healthcare systems worldwide, often requiring significant human and financial resources. Chronic wounds arise from the complex interplay of underlying comorbidities, such as diabetes or vascular diseases, lifestyle factors, and genetic risk profiles which may predispose extremities to local ischemia. Injuries are further exacerbated by bacterial colonization and the formation of biofilms. Infection, consequently, perpetuates a chronic inflammatory microenvironment, preventing the progression and completion of normal wound healing. The current standard of care (SOC) for chronic wounds involves surgical debridement along with localized wound irrigation, which requires inpatient care under general anesthesia. This could be followed by, if necessary, defect coverage via a reconstructive ladder utilizing wound debridement along with skin graft, local, or free flap techniques once the wound conditions are stabilized and adequate blood supply is restored. To promote physiological wound healing, a variety of approaches have been subjected to translational research. Beyond conventional wound healing drugs and devices that currently supplement treatments, cellular and immunotherapies have emerged as promising therapeutics that can behave as tailored therapies with cell- or molecule-specific wound healing properties. However, in contrast to the clinical omnipresence of chronic wound healing disorders, there remains a shortage of studies condensing the current body of evidence on cellular therapies and immunotherapies for chronic wounds. This review provides a comprehensive exploration of current therapies, experimental approaches, and translational studies, offering insights into their efficacy and limitations. Ultimately, we hope this line of research may serve as an evidence-based foundation to guide further experimental and translational approaches and optimize patient care long-term.

Circuit mechanism underlying fragmented sleep and memory deficits in 16p11.2 deletion mouse model of autism.

Sleep disturbances are prevalent in children with autism spectrum disorder (ASD) and have a major impact on the quality of life. Strikingly, sleep problems are positively correlated with the severity of ASD symptoms, such as memory impairment. However, the neural mechanisms underlying sleep disturbances and cognitive deficits in ASD are largely unexplored. Here, we show that non-rapid eye movement sleep (NREMs) is highly fragmented in the 16p11.2 deletion mouse model of ASD. The degree of sleep fragmentation is reflected in an increased number of calcium transients in the activity of locus coeruleus noradrenergic (LC-NE) neurons during NREMs. Exposure to a novel environment further exacerbates sleep disturbances in 16p11.2 deletion mice by fragmenting NREMs and decreasing rapid eye movement sleep (REMs). In contrast, optogenetic inhibition of LC-NE neurons and pharmacological blockade of noradrenergic transmission using clonidine reverse sleep fragmentation. Furthermore, inhibiting LC-NE neurons restores memory. Rabies-mediated unbiased screening of presynaptic neurons reveals altered connectivity of LC-NE neurons with sleep- and memory regulatory brain regions in 16p11.2 deletion mice. Our findings demonstrate that heightened activity of LC-NE neurons and altered brain-wide connectivity underlies sleep fragmentation in 16p11.2 deletion mice and identify a crucial role of the LC-NE system in regulating sleep stability and memory in ASD.

Circuit mechanism underlying fragmented sleep and memory deficits in 16p11.2 deletion mouse model of autism.

Sleep disturbances are prevalent in children with autism spectrum disorder (ASD) and have a major impact on the quality of life. Strikingly, sleep problems are positively correlated with the severity of ASD symptoms, such as memory impairment. However, the neural mechanisms underlying sleep disturbances and cognitive deficits in ASD are largely unexplored. Here, we show that non-rapid eye movement sleep (NREMs) is highly fragmented in the 16p11.2 deletion mouse model of ASD. The degree of sleep fragmentation is reflected in an increased number of calcium transients in the activity of locus coeruleus noradrenergic (LC-NE) neurons during NREMs. Exposure to a novel environment further exacerbates sleep disturbances in 16p11.2 deletion mice by fragmenting NREMs and decreasing rapid eye movement sleep (REMs). In contrast, optogenetic inhibition of LC-NE neurons and pharmacological blockade of noradrenergic transmission using clonidine reverse sleep fragmentation. Furthermore, inhibiting LC-NE neurons restores memory. Rabies-mediated unbiased screening of presynaptic neurons reveals altered connectivity of LC-NE neurons with sleep- and memory regulatory brain regions in 16p11.2 deletion mice. Our findings demonstrate that heightened activity of LC-NE neurons and altered brain-wide connectivity underlies sleep fragmentation in 16p11.2 deletion mice and identify a crucial role of the LC-NE system in regulating sleep stability and memory in ASD.

Regulation of stress-induced sleep fragmentation by preoptic glutamatergic neurons.

Sleep disturbances are detrimental to our behavioral and emotional well-being. Stressful events disrupt sleep, in particular by inducing brief awakenings (microarousals, MAs), resulting in sleep fragmentation. The preoptic area of the hypothalamus (POA) is crucial for sleep control. However, how POA neurons contribute to the regulation of MAs and thereby impact sleep quality is unknown. Using fiber photometry in mice, we examine the activity of genetically defined POA subpopulations during sleep. We find that POA glutamatergic neurons are rhythmically activated in synchrony with an infraslow rhythm in the spindle band of the electroencephalogram during non-rapid eye movement sleep (NREMs) and are transiently activated during MAs. Optogenetic stimulation of these neurons promotes MAs and wakefulness. Exposure to acute social defeat stress fragments NREMs and significantly increases the number of transients in the calcium activity of POA glutamatergic neurons during NREMs. By reducing MAs, optogenetic inhibition during spontaneous sleep and after stress consolidates NREMs. Monosynaptically restricted rabies tracing reveals that POA glutamatergic neurons are innervated by brain regions regulating stress and sleep. In particular, presynaptic glutamatergic neurons in the lateral hypothalamus become activated after stress, and stimulating their projections to the POA promotes MAs and wakefulness. Our findings uncover a novel circuit mechanism by which POA excitatory neurons regulate sleep quality after stress.

The Pterional Keyhole Craniotomy Approach: A Historical Perspective.

The pterional craniotomy is a workhorse of cranial surgery that provides access to the anterior and middle fossae. However, newer "keyhole" approaches, such as the micropterional or pterional keyhole craniotomy (PKC) can offer similar exposure for many pathologies while reducing surgical morbidity. The PKC is associated with shorter hospitalizations, reduced operative time, and superior cosmetic outcomes. Furthermore, it represents an ongoing trend toward smaller craniotomy size for elective cranial procedures. In this historical vignette, we trace the history of the PKC from its origins to its current role in the neurosurgeon's armamentarium.

Phospholipid scramblase-1 regulates innate type 2 inflammation in mouse lungs via CRTH2-dependent mechanisms.

Exaggerated Type 2 immune responses play critical roles in the pathogenesis of a variety of diseases including asthma, allergy, and pulmonary fibrosis. Recent studies have highlighted the importance of innate type 2 immune responses and innate lymphoid 2 cells (ILC2s) in these disorders. However, the mechanisms that control the development of pulmonary innate type 2 responses (IT2IR) and the recruitment and/or activation of ILC2 cells are poorly understood. In mouse models of pulmonary IT2IR, we demonstrated that phospholipid scramblase-1 (PLSCR1), a type II transmembrane protein that mediates bidirectional and nonspecific translocation of phospholipids between the inner and outer leaflets of the plasma membrane, was a critical regulator of IT2IR in the lung. We further suggested that (a) PLSCR1 bound to and physically interacted with chemoattractant receptor-homologous molecule(CRTH2), which is a G-protein-coupled receptor that is expressed on TH2 cells and on multiple immune cells and is commonly used to identify ILC2 cells, and (b) the effects of PLSCR1 on ILC2 activation and IT2IR were mediated via CRTH2-dependent mechanisms. Overall, our studies demonstrated that PLSCR1 played an essential role in the pathogenesis of ILC2 responses, providing critical insights into biology and disease pathogenesis and identifying targets that can be manipulated in attempts to control IT2IR in chronic diseases such as asthma.

Tracheal stenosis and airway complications in the Coronavirus Disease-19 era.

BACKGROUND: Severe Coronavirus Disease 2019 (COVID-19) infection is associated with prolonged intubation and its complications. Tracheal stenosis is one such complication that may require specialized surgical management. We aimed to describe the surgical management of post-COVID-19 tracheal stenosis. METHODS: This case series describes consecutive patients with tracheal stenosis from intubation for severe COVID-19 infection at our single, tertiary academic medical center between January 1st, 2021, and December 31st, 2021. Patients were included if they underwent surgical management with tracheal resection and reconstruction, or bronchoscopic intervention. Operative through six-month, symptom-free survival and histopathological analysis of resected trachea were reviewed. RESULTS: Eight patients are included in this case series. All patients are female, and most (87.5%) are obese. Five patients (62.5%) underwent tracheal resection and reconstruction (TRR), while three patients (38.5%) underwent non-resection-based management. Among patients who underwent TRR, six-month symptom free survival is 80%; one patient (20%) required tracheostomy after TRR due to recurrent symptoms. Two of the three (66.7%) of patients who underwent non-resection-based management experienced durable relief from symptoms of tracheal stenosis with tracheal balloon dilation, and the remaining patient required laser excision of tracheal tissue prior to experiencing symptomatic relief. CONCLUSIONS: The incidence of tracheal stenosis may increase as patients recover from severe COVID-19 infection requiring intubation. Management of tracheal stenosis with TRR is safe and effective, with comparable rates of success to TRR for non-COVID-19 tracheal stenosis. Non-resection-based management is an option to manage tracheal stenosis in patients with less severe stenosis or in poor surgical candidates.

Sleep disturbances in autism spectrum disorder: Animal models, neural mechanisms, and therapeutics.

Sleep is crucial for brain development. Sleep disturbances are prevalent in children with autism spectrum disorder (ASD). Strikingly, these sleep problems are positively correlated with the severity of ASD core symptoms such as deficits in social skills and stereotypic behavior, indicating that sleep problems and the behavioral characteristics of ASD may be related. In this review, we will discuss sleep disturbances in children with ASD and highlight mouse models to study sleep disturbances and behavioral phenotypes in ASD. In addition, we will review neuromodulators controlling sleep and wakefulness and how these neuromodulatory systems are disrupted in animal models and patients with ASD. Lastly, we will address how the therapeutic interventions for patients with ASD improve various aspects of sleep. Together, gaining mechanistic insights into the neural mechanisms underlying sleep disturbances in children with ASD will help us to develop better therapeutic interventions.

Comparison of Male and Female Surgeons' Experiences With Gender Across 5 Qualitative/Quantitative Domains.

Importance: A growing body of literature has been developed with the goal of attempting to understand the experiences of female surgeons. While it has helped to address inequities and promote important programmatic improvements, work remains to be done. Objective: To explore how practicing male and female surgeons' experiences with gender compare across 5 qualitative/quantitative domains: career aspirations, gender-based discrimination, mentor-mentee relationships, perceived barriers, and recommendations for change. Design, Setting, and Participants: This national concurrent mixed-methods survey of Fellows of the American College of Surgeons (FACS) compared differences between male and female FACS. Differences between female FACS and female members of the Association of Women Surgeons (AWS) were also explored. A randomly selected 3:1 sample of US-based male and female FACS was surveyed between January and June 2020. Female AWS members were surveyed in May 2020. Exposure: Self-reported gender. Main Outcomes and Measures: Self-reported experiences with career aspirations (quantitative), gender-based discrimination (quantitative), mentor-mentee relationships (quantitative), perceived barriers (qualitative), and recommendations for change (qualitative). Results: A total of 2860 male FACS (response rate: 38.1% [2860 of 7500]) and 1070 female FACS (response rate: 42.8% [1070 of 2500]) were included, in addition to 536 female AWS members. Demographic characteristics were similar between randomly selected male and female FACS, with the notable exception that female FACS were less likely to be married (720 [67.3%] vs 2561 [89.5%]; nonresponse-weighted P < .001) and have children (660 [61.7%] vs 2600 [90.9%]; P < .001). Compared with female FACS, female AWS members were more likely to be younger and hold additional graduate degrees (320 [59.7%] were married; 238 [44.4%] had children). FACS of both genders acknowledged positive and negative aspects of dealing with gender in a professional setting, including shared experiences of gender-based harassment, discrimination, and blame. Female FACS were less likely to have had gender-concordant mentors. They were more likely to emphasize the importance of gender when determining career aspirations and prioritizing future mentor-mentee relationships. Moving forward, female FACS emphasized the importance of avoiding competition among female surgeons. They encouraged male surgeons to acknowledge gender bias and admit their potential role. Male FACS encouraged male and female surgeons to treat everyone the same. Conclusions and Relevance: Experiences with gender are not limited to supportive female surgeons. The results of this study emphasize the importance of recognizing the voices of all stakeholders involved when striving to promote workforce diversity and the related need to develop quality improvement/surgical education initiatives that enhance inclusion through open, honest discourse.

Ubiquitinated PCNA Drives USP1 Synthetic Lethality in Cancer.

CRISPR Cas9-based screening is a powerful approach for identifying and characterizing novel drug targets. Here, we elucidate the synthetic lethal mechanism of deubiquitinating enzyme USP1 in cancers with underlying DNA damage vulnerabilities, specifically BRCA1/2 mutant tumors and a subset of BRCA1/2 wild-type (WT) tumors. In sensitive cells, pharmacologic inhibition of USP1 leads to decreased DNA synthesis concomitant with S-phase-specific DNA damage. Genome-wide CRISPR-Cas9 screens identify RAD18 and UBE2K, which promote PCNA mono- and polyubiquitination respectively, as mediators of USP1 dependency. The accumulation of mono- and polyubiquitinated PCNA following USP1 inhibition is associated with reduced PCNA protein levels. Ectopic expression of WT or ubiquitin-dead K164R PCNA reverses USP1 inhibitor sensitivity. Our results show, for the first time, that USP1 dependency hinges on the aberrant processing of mono- and polyubiquitinated PCNA. Moreover, this mechanism of USP1 dependency extends beyond BRCA1/2 mutant tumors to selected BRCA1/2 WT cancer cell lines enriched in ovarian and lung lineages. We further show PARP and USP1 inhibition are strongly synergistic in BRCA1/2 mutant tumors. We postulate USP1 dependency unveils a previously uncharacterized vulnerability linked to posttranslational modifications of PCNA. Taken together, USP1 inhibition may represent a novel therapeutic strategy for BRCA1/2 mutant tumors and a subset of BRCA1/2 WT tumors.

A noradrenergic-hypothalamic neural substrate for stress-induced sleep disturbances.

In our daily life, we are exposed to uncontrollable and stressful events that disrupt our sleep. However, the underlying neural mechanisms deteriorating the quality of non-rapid eye movement sleep (NREMs) and REM sleep are largely unknown. Here, we show in mice that acute psychosocial stress disrupts sleep by increasing brief arousals (microarousals [MAs]), reducing sleep spindles, and impairing infraslow oscillations in the spindle band of the electroencephalogram during NREMs, while reducing REMs. This poor sleep quality was reflected in an increased number of calcium transients in the activity of noradrenergic (NE) neurons in the locus coeruleus (LC) during NREMs. Opto- and chemogenetic LC-NE activation in naïve mice is sufficient to change the sleep microarchitecture similar to stress. Conversely, chemogenetically inhibiting LC-NE neurons reduced MAs during NREMs and normalized their number after stress. Specifically inhibiting LC-NE neurons projecting to the preoptic area of the hypothalamus (POA) decreased MAs and enhanced spindles and REMs after stress. Optrode recordings revealed that stimulating LC-NE fibers in the POA indeed suppressed the spiking activity of POA neurons that are activated during sleep spindles and REMs and inactivated during MAs. Our findings reveal that changes in the dynamics of the stress-regulatory LC-NE neurons during sleep negatively affect sleep quality, partially through their interaction with the POA.

The minimally conscious state: an analysis of current clinical trials registered in ClinicalTrials.gov.

The minimally conscious state (MCS) is a disorder of consciousness described in recent years for patients who have behavioral responses to stimuli that do not meet the classification of chronic vegetative state (CVS) or coma. This distinction is valuable in clinical practice, as minimally conscious patients may require different treatments and may have different long-term outcomes when compared to vegetative states or coma. In this report, we analyzed the ClinicalTrials.gov database to systematically assess all clinical trials regarding MCS. The database was queried using the term "minimally conscious state" in the "condition or disease" search parameter. Of the studies identified, those that had suspended, terminated, or otherwise unknown statuses were excluded. In total, 41 studies were analyzed. The included studies were initiated between 2008 and 2020, with the majority (63%) beginning in 2015 or later. Of the primary intervention modalities included, 15 (37%) evaluated stimulation modalities such as transcranial magnetic stimulation, transcranial direct current stimulation, implantable neurostimulation, vagus nerve stimulation, focused ultrasound and median nerve stimulation. Additionally, 5 (12%) used some form of behavioral therapy. A total of 4 (10%) studies involved pharmaceutical intervention, including dopamine agonists, analgesics and sedatives. Finally, 4 (10%) studies sought to determine the validity of current diagnostic methods and systems used to assess the status of patients in MCSs. Since the definition and criteria for CVS and MCS have been established, these two conditions remain closely associated despite evidence of different patient outcomes and treatment options. Many clinical trials are underway assessing interventions with stimulation. However, the trials are lacking with respect to diagnostic methods and pharmaceutical treatment.

Supraorbital Keyhole Craniotomy in Pediatric Neurosurgery: A Systematic Review of Clinical Outcomes and Cosmetic Outcomes.

BACKGROUND: Supraorbital keyhole craniotomy is a minimally invasive approach used to access the parasellar region with advantages of decreased cortical exposure, simple closure, and decreased risk of postoperative cerebrospinal fluid leak. The incision of this approach, however, has raised cosmetic concerns, especially for pediatric patients. The aim of this study is to assess postoperative complications and cosmeses of the supraorbital keyhole approach for resection of intracranial lesions in pediatric patients. METHODS: A literature search of PubMed, Scopus, and Web of Science databases was performed on June 1, 2021, searching for all studies of pediatric patients undergoing supraorbital keyhole craniotomy for surgical resection of lesions in the anterior fossa/sellar region. RESULTS: Of 729 unique hits, 15 supraorbital keyhole studies reporting on 177 pediatric cases were included in the final review. Quality of all included studies was moderate. Overall, the surgery was well tolerated with a low number of severe adverse events. A wide variety of pathologies were treated with this approach. Complications of surgery included changes in vision, epidural hematoma, subdural hematoma, cerebrospinal fluid leak, and wound infection. At 6 weeks of follow-up, surgical scars in most patients were noted to be minimally detectable. At 3-6 months of follow-up, scars were no longer visible. Cosmetic complications included 5 bone defects, 1 split eyebrow, and 1 case of ptosis. CONCLUSIONS: This study suggests that supraorbital keyhole craniotomy is a safe and effective approach to access the parasellar region in pediatric patients with excellent cosmetic outcomes reported across multiple institutions.

Lung Transplantation After Ex Vivo Lung Perfusion Early Outcomes From a US National Registry.

OBJECTIVE: The objective of this study was to examine early lung transplant outcomes following EVLP using a large national transplant registry. SUMMARY OF BACKGROUND DATA: Lung transplantation in the United States continues to be constrained by a limited supply of donor organs. EVLP has the potential to significantly increase the available pool of donor lung allografts through the reconditioning of "marginal" organs. METHODS: The united network for organ sharing registry was queried for all adults (age ≥18) who underwent first-time lung transplantation between March 2018 (when united network for organ sharing began collecting confirmed donor EVLP status) and June 2019. Transplants were stratified by EVLP use. The primary outcome was short-term survival and secondary outcomes included acute rejection before discharge and need for extracorpo-real membrane oxygenation support post-transplant. RESULTS: A total of 3334 recipients met inclusion criteria including 155 (5%) and 3179 (95%) who did and did not receive allografts that had undergone EVLP, respectively. On unadjusted descriptive analysis, EVLP and non-EVLP cohorts had similar 180-day survival (92% vs 92%, P = 0.9). EVLP use was associated with a similar rate of acute rejection (13% vs 9%, P = 0.08) but increased rate of early extracorporeal membrane oxygenation use (12% vs 7%, P = 0.04). After adjustment, EVLP use was not associated with significantly increased mortality (adjusted hazard ratio 0.99, 95% confidence interval 0.62-1.58) or acute rejection (adjusted odds ratio 0.89, 95% confidence interval 0.40-1.97) compared to non-EVLP use. CONCLUSIONS: In the largest national series of EVLP lung transplant recipients, EVLP is associated with early recipient outcomes comparable to that of non-EVLP recipients with similar baseline characteristics. Longer term follow-up data is needed to further assess the impact of EVLP on post-lung transplant outcomes.