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The interplay between mesenchymal stem/stromal cells (MSCs) and preservation conditions is critical to maintain the viability and functionality of these cells before administration. We observed that Ringer lactate (RL) maintained high viability of bone marrow–derived MSCs for up to 72 h at room temperature (18°C–22°C), whereas adipose‐derived and umbilical cord‐derived MSCs showed the highest viability for 72 h at a cold temperature (4°C–8°C). These cells maintained their adherence ability with an improved recovery rate and metabolic profiles (glycolysis and mitochondrial respiration) similar to those of freshly harvested cells. Growth factor and cytokine analyses revealed that the preserved cells released substantial amounts of leukaemia inhibitory factors (LIFs), hepatocyte growth factor (HGF) and vascular endothelial growth factor‐A (VEGF‐A), as well as multiple cytokines (eg IL‐4, IL‐6, IL‐8, MPC‐1 and TNF‐α). Our data provide the simplest clinically relevant preservation conditions that maintain the viability, stemness and functionality of MSCs from perinatal and adult tissue sources.

AIM Paediatric emergency departments (ED) nationwide experience a shared burden of boarding mental health patients. Whilst boarding, some patients have a change in disposition from hospitalization to discharge home. This phenomenon raises concern because EDs often have scarce resources for mental health patients. We sought to understand which patient and clinical factors are associated with a change in disposition outcome. METHODS A nested age-sex-race frequency-matched case-control study was conducted including paediatric patients who presented to an urban PED for mental healthcare over a 36-month period. Control patients included patients admitted to an inpatient psychiatric facility, whilst case patients were those discharged home. Descriptive statistics and multivariable logistic regression analyses were performed to compare groups. RESULTS Case patients were more likely to receive intramuscular Haloperidol (OR 2.2 [CI 1.1-4.4]) for agitation and a psychiatric consult (OR 2.3 [1.4-3.9]) whilst boarding. Case patients were also more likely to present with behavioural concerns (OR 1.8 [CI 1.1-3.1]) and have additional complexities such as medical comorbidities (OR 1.8 [CI 1.1-2.9]) or suicidal ideation/attempt (OR 2.6 [CI 1.1-6.1]). Amongst the most common themes for disposition change was improved patient status (58.8%). CONCLUSION These findings suggest that boarding mental health patients have different disposition outcomes and thus may benefit from patient-specific treatment interventions. Given that patients' statuses may change during the boarding period prompting discharge to home, more focus should be directed to developing brief evidence-based practises that may be implemented in the ED and effectively bridge the gap to outpatient mental health services.

The physiological role of T cell anergy induction as a key mechanism supporting self-tolerance remains undefined, and natural antigens that induce anergy are largely unknown. In this report, we used TCR sequencing to show that the recruitment of CD4+CD44+Foxp3-CD73+FR4+ anergic (Tan) cells expands the CD4+Foxp3+ (Tregs) repertoire. Next, we report that blockade in peripherally-induced Tregs (pTregs) formation due to mutation in CNS1 region of Foxp3 or chronic exposure to a selecting self-peptide result in an accumulation of Tan cells. Finally, we show that microbial antigens from Akkermansia muciniphila commensal bacteria can induce anergy and drive conversion of naive CD4+CD44-Foxp3- T (Tn) cells to the Treg lineage. Overall, data presented here suggest that Tan induction helps the Treg repertoire to become optimally balanced to provide tolerance toward ubiquitous and microbiome-derived epitopes, improving host ability to avert systemic autoimmunity and intestinal inflammation.

Interleukin 36 (IL‐36) constitutes a group of cytokines that belong to the IL‐1 superfamily. Emerging evidence has suggested a role of IL‐36 in the pathogenesis of many inflammatory disorders. Intriguingly, in the gastrointestinal tract, IL‐36 has a rather complex function. IL‐36 receptor ligands are overexpressed in both animal colitis models and human IBD patients and may play both pathogenic and protective roles, depending on the context. IL‐36 cytokines comprise three receptor agonists: IL‐36α, IL‐36β and IL‐36γ, and two receptor antagonists: IL‐36Ra and IL‐38. All IL‐36 receptor agonists bind to the IL‐36R complex and exert pleiotropic effects during inflammatory settings. Here, we first briefly review the processing and secretion of IL‐36 cytokines. We then focus on the current understanding of the immunology effects of IL‐36 in gut immunity. In addition, we also discuss the ongoing trials that aim to blockage IL‐36R signalling for treating chronic intestinal inflammation and present some unexplored questions regarding IL‐36 research.

Enteropathogenic bacterial infections are a global health issue associated with high mortality, particularly in developing countries. Efficient host protection against enteropathogenic bacterial infection is characterized by coordinated responses between immune and nonimmune cells. In response to infection in mice, innate immune cells are activated to produce interleukin (IL)-23 and IL-22, which promote antimicrobial peptide (AMP) production and bacterial clearance. IL-36 cytokines are proinflammatory IL-1 superfamily members, yet their role in enteropathogenic bacterial infection remains poorly defined. Using the enteric mouse pathogen, C. rodentium, we demonstrate that signaling via IL-36 receptor (IL-36R) orchestrates a crucial innate-adaptive immune link to control bacterial infection. IL-36R-deficient mice (Il1rl2(−/−)) exhibited significant impairment in expression of IL-22 and AMPs, increased intestinal damage, and failed to contain C. rodentium compared to controls. These defects were associated with failure to induce IL-23 and IL-6, two key IL-22 inducers in the early and late phases of infection, respectively. Treatment of Il1rl2(−/−) mice with IL-23 during the early phase of C. rodentium infection rescued IL-22 production from group 3 innate lymphoid cells (ILCs), whereas IL-6 administration during the late phase rescued IL-22-mediated production from CD4(+) T cell, and both treatments protected Il1rl2(−/−) mice from uncontained infection. Furthermore, IL-36R-mediated IL-22 production by CD4(+) T cells was dependent upon NFκB-p65 and IL-6 expression in dendritic cells (DCs), as well as aryl hydrocarbon receptor (AhR) expression by CD4(+) T cells. Collectively, these data demonstrate that the IL-36 signaling pathway integrates innate and adaptive immunity leading to host defense against enteropathogenic bacterial infection.

Purpose of Review This is a comprehensive review of the current literature on the usage of galcanezumab for migraine treatment. It reviews the biology, pathophysiology, epidemiology, diagnosis, and conventional treatment of migraines, then compares the literature available for galcanezumab with historical treatment options. Recent Findings Migraine is a common headache disorder and constitutes a significant source of distress from both a personal and societal perspective. Conventional treatment includes abortive and preventive treatment. Treatment options are limited and may be only partially or minimally effective in some of the population. Recent evidence points to metabolic changes in the brain as possible causes of migraine, via reduced available energy or a spiking need for it, resulting in a relative insufficiency. This leads to trigeminocervical complex (TCC) activation and a headache episode, modulated by calcitonin gene-related peptide (CGRP). Galcanezumab (Emgality) is a monoclonal antibody targeting CGRP that is given in a monthly injection for the prevention of migraines. Its safety was previously shown in phase 1 and 2 trials, and recent phase 3 trials showed efficacy, with up to 50% reduction in monthly migraine days and improved functional capacity in migraineurs. Studies show that the drug is well tolerated and safe. Summary Migraine headache is a common neurological syndrome that causes great pain and suffering. Treatment options today are limited. Galcanezumab does not prevent migraines, but it is effective in decreasing their frequency and length. It is also much better tolerated than the currently existing therapies. While it is unlikely to provide monotherapy for migraines, it is a novel therapy that may be added for cases of severe or frequent migraines.

The mechanism of how plant-derived nanovesicles are uptaken by cells remains unknown. In this study, the garlic-derived nanovesicles (GDVs) were isolated and digested with trypsin to remove all surface proteins. Digested GDVs showed less uptake compared to undigested GDVs, confirming that the surface proteins played a role in the endocytosis. On the cell side (HepG2), interestingly, blocking the CD98 receptors significantly reduced the uptake of GDVs. During the cellular internalization of GDVs, we observed that some surface proteins of GDVs were co-localized with CD98. A total lysate of the GDV surface showed a high presence of a mannose-specific binding protein, II lectin. Blocking GDV II lectin (using mannose preincubation) highly reduced the GDV internalization, which supports that direct interaction between II lectin and CD98 plays an important role in internalization. The GDVs also exhibited in vitro anti-inflammatory effect by downregulating proinflammatory factors on the HepG2 cells. This work contributes to understanding a part of the GDV internalization process and the cellular anti-inflammatory effects of garlic.

OBJECTIVES Spinal cord stimulation (SCS) therapies are used in the management of patients with complex regional pain syndrome I (CRPS I) and failed back surgery syndrome (FBSS). The purpose of this study was to investigate the racial and health insurance inequalities with SCS therapy in patients with chronic pain who had CRPS I and FBSS. METHODS Patients with chronic pain who had a discharge diagnosis of FBSS and CRPS I were identified using the National Inpatient Sample database. Our primary outcome was defined as the history of SCS utilization by race/ethnicity, income quartile, and insurance status. Multivariable logistic regression was used to determine the variables associated with utilization of SCS therapy. RESULTS Between 2011 and 2015, 40,858 patients who were hospitalized with a primary diagnosis of FBSS and/or CRPS I were identified. Of these patients, 1,082 (2.7%) had a history of SCS therapy. Multivariable regression analysis revealed that compared to White patients, Black and Hispanic patients had higher odds of having SCS therapy (Black patients: odds ratio [OR] = 1.41; 95% confidence interval [CI], 1.12 to 1.77; P = 0.003; Hispanic patients: OR = 1.41; 95% CI, 1.10 to 1.81; P = 0.007). Patients with private insurance had significantly higher odds of having SCS therapy compared with those with Medicare (OR = 1.24; 95% CI, 1.08 to 1.43; P = 0.003). Compared to patients with Medicare, Medicaid patients had lower odds of having SCS therapy (OR = 0.50; 95% CI, 0.36 to 0.70; P

Purpose of Review This is a comprehensive review of the literature about the use of bupivacaine hydrochloride for the treatment of post-herpetic neuralgia (PHN). It briefly reviews the background, biology, diagnosis and conventional treatment for PHN, and then introduces and compares the recent evidence for the use of topical bupivacaine. Recent Findings PHN is defined by pain lasting 90 days or more after the initial presentation of herpes zoster (“Shingles”, HZ) rash and is the most common complication of this disease. A product of re-activation of the Varicella-Zoster virus (VZV), HZ is diagnosed more than 1 million times annually in the United States. Approximately 20% of patients with HZ will experience PHN and will continue to suffer intermittent neuropathic symptoms, including itching and pain, that is sharp, stabbing, throbbing or burning, with the pain localized to the site of their original rash. This long-lasting pain compares with the severity of long-standing rheumatics and osteo-arthritis and is accompanied by severe allodynia causing significant suffering, and a financial burden that is manifested in both healthcare costs and loss of quality-adjusted life years. Prevention of PHN may be achieved with the Zoster vaccine, although there is still a large segment of unvaccinated population. Moreover, the Zoster vaccine is not always effective for prevention. Current treatment includes medical (systemic tricyclic antidepressants, anticonvulsants and opioids, topical lidocaine and capsaicin) and interventional (subcutaneous Botox injections, nerve blocks and nerve stimulation) therapies. These therapies are not always effective, and each carries their own profile of side effects and risks. Moreover, up to 50% of patients with PHN are refractory to management. Recent evidence is emerging to support the use of topical local anesthetics for the treatment of PHN. Two small studies recently found topical lidocaine spray to be effective in treating paroxysmal pain attacks associated with PHN. Bupivacaine is a longer-lasting local anesthetic, and a film-forming formulation allows easy and durable application to the affected skin. Recent studies show that topical film-forming bupivacaine is safe and as effective as lidocaine for the treatment of PHN. Summary PHN is an important though common complication of HZ and can cause long-lasting pain and disability. Current treatment for PNH is limited by efficacy and safety profiles of individual therapies. Recent evidence points to topical local anesthetics as an effective and safe alternative to conventional therapy. Film-forming bupivacaine may offer a durable and safe option for this otherwise difficult to treat syndrome.

Purpose This is a comprehensive review of the current literature on central neuropathic pain mechanisms that is secondary to spinal cord injury. It reviews recent and seminal findings on the pathophysiology, diagnosis, and treatment and compares treatment options and recommendations. Recent Findings Neuropathic pain (NP) is a common complication of spinal cord injury (SCI). Chronicity of NP is attributed to increased abundance of inflammatory mediators and ion channel dysfunction leading to afferent nerve sensitization; nerve damage and nerve–glia cross talk have also been implicated. Conventional treatment is medical and has had limited success. Recent studies have made headway in identifying novel biomarkers, including microRNA and psychosocial attributes that can predict progress from SCI to chronic NP (CNP). Recent advances have provided evidence of efficacy for two promising drugs. Baclofen was able to provide good, long-lasting pain relief. Ziconotide, a voltage-gated calcium channel blocker, was studied in a small trial and was able to provide good analgesia in most participants. However, several participants had to be withdrawn because of worrisome creatine phosphokinase (CPK) elevations, and further studies are required to define its safety profile. Non-medical interventions include brain sensitization and biofeedback techniques. These methods have recently had encouraging results, albeit preliminary. Case reports of non-conventional techniques, such as hypnosis, were also reported. Summary CNP is a common complication of SCI and is a prevalent disorder with significant morbidity and disability. Conventional medical treatment is limited in efficacy. Recent studies identified baclofen and ziconotide as possible new therapies, alongside non-medical interventions. Further research into the pathophysiology is required to identify further therapy candidates. A multidisciplinary approach, including psychosocial support, medical and non-medical interventions, is likely needed to achieve therapeutic effects in this difficult to treat syndrome.

Migraine headache is a common, chronic, debilitating disease with a complex etiology. Current therapy for migraine headache comprises either treatments targeting acute migraine pain or prophylactic therapy aimed at increasing the length of time between migraine episodes. Recent evidence suggests that calcium gene-related peptide (CGRP) is a critical component in the pathogenesis of migraines. Fremanezumab, a monoclonal antibody against CGRP, was recently approved by the Food and Drug Administration (FDA) after multiple studies showed that it was well-tolerated, safe, and effective in the treatment of migraines. Further research is needed to elucidate the long-term effects of fremanezumab and CGRP-antagonists in general, and additional data is required in less healthy patients to estimate its effects in these populations and potentially increase the eligible group of recipients. This is a comprehensive review of the current literature on the efficacy and safety of fremanezumab for the treatment of chronic migraine. In this review we provide an update on the epidemiology, pathogenesis, diagnosis, and current treatment of migraine, and summarize the evidence for fremanezumab as a treatment for migraine.

Introduction Cosmetic breast surgery is commonly performed in the United States; 520,000 procedures of the total 1.8 million cosmetic surgical procedures performed in 2018 were breast related. Postoperative chronic pain, defined as lasting 3 or more months, has been reported in a wide variety of breast surgical procedures including breast augmentation, reduction mammaplasty, mastectomy, and mastectomy with reconstruction. Patient characteristics associated with the development of postoperative chronic pain following cosmetic breast surgery include a younger age, larger BMI, smaller height, postoperative hyperesthesia, and elevated baseline depression, anxiety, and catastrophizing scores. The anatomical distribution of chronic pain following breast augmentation procedures is dependent upon incision site placement; pectoral and intercostal nerves have been implicated. The purpose of this review is to provide an update on the current literature addressing the pathophysiology, clinical presentation, and treatment of patients presenting with chronic postoperative pain following cosmetic breast surgery. Methods A comprehensive literature review was performed in MEDLINE, PubMed, and Cochrane databases from 1996 to 2019 using the terms “cosmetic surgery”, “breast surgery”, “postoperative pain”, and “chronic pain”. Results Cosmetic breast surgery can have a similar presentation as post-mastectomy pain syndrome and thus have overlapping diagnostic criteria. Seven domains are identified for a diagnosis of PBSPS: Pain after breast surgery, neuropathic in nature, at least a moderate intensity of pain, as defined as within the middle one-third of the selected pain scale, pain for at least 6 months, symptoms occurring for 12 or more hours a day for a minimum of 4 days each week, pain in at least one of the following sites: breast, chest wall, axilla, or arm on the affected side, pain exacerbated by movement. Patient risk factors and surgical risk factors may influence the development of chronic post-cosmetic surgery breast pain. Improved perioperative analgesia including preoperative regional nerve anesthesia and postoperative catheter infusion have been shown to improve chronic postoperative pain outcomes. Conclusions The present review provides a discussion of clinical presentation, pathophysiology, and treatment and preventative strategies for chronic breast pain following cosmetic surgery. This review provides evidence from multiple randomized controlled trials (RCTs) and systematic reviews of efficacy and effectiveness. While chronic postoperative breast pain remains challenging to treat, various preventative strategies have been described to improve postoperative pain outcomes.

Resident and attending concern about the potential for decreased teaching has been cited as one of the drawbacks to the adoption of family-centered rounds (FCR). Despite these concerns, FCR can enhance clinical education through direct exposure to multiple patients by all team members, as well as by allowing faculty to teach, model, observe, and assess learners' clinical skills more effectively than in nonbedside settings. This article provides many strategies and approaches to bedside teaching designed to enhance education and communication among care team members as well as patients and their families.

Incorporation of membrane-anchored flagellin molecules into the surfaces of influenza virus-like particles (VLP) was previously reported to promote T helper (Th) 1-biased IgG antibody production and protective efficacy of co-presented vaccine antigens. Herein, we investigated the potential adjuvant effects and mechanisms of flagellin-expressing VLP (FliC-VLP) as an independent component on influenza vaccination in wild-type and mutant mouse models. FliC-VLP adjuvanted influenza vaccination was highly effective in promoting the induction of Th1-biased IgG isotype switched antibodies, enhanced protection, and long-lasting IgG antibody responses in both wild-type and CD4-knockout mice. In contrast, the adjuvant effects of soluble flagellin were Th2-biased and required CD4 T helper cells. The adjuvant effects of FliC-VLP were less dependent on CD4 T cells and flagellin-mediated innate immune signaling pathways. The results suggest that FliC-VLP might play an effective adjuvant role in an immune competent condition as well as in a defect of CD4 T cells.

Background & Aims Nourishment of gut microbiota via consumption of fermentable fiber promotes gut health and guards against metabolic syndrome. In contrast, how dietary fiber impacts type 1 diabetes is less clear. Methods To examine impact of dietary fibers on development of type 1 diabetes in the streptozotocin (STZ)-induced and spontaneous non-obese diabetes (NOD) models, mice were fed grain-based chow (GBC) or compositionally defined diets enriched with a fermentable fiber (inulin) or an insoluble fiber (cellulose). Spontaneous (NOD mice) or STZ-induced (wild-type mice) diabetes was monitored. Results Relative to GBC, low-fiber diets exacerbated STZ-induced diabetes, whereas diets enriched with inulin, but not cellulose, strongly protected against or treated it. Inulin’s restoration of glycemic control prevented loss of adipose depots, while reducing food and water consumption. Inulin normalized pancreatic function and markedly enhanced insulin sensitivity. Such amelioration of diabetes was associated with alterations in gut microbiota composition and was eliminated by antibiotic administration. Pharmacologic blockade of fermentation reduced inulin’s beneficial impact on glycemic control, indicating a role for short-chain fatty acids (SCFA). Furthermore, inulin’s microbiota-dependent anti-diabetic effect associated with SCFA-independent restoration of interleukin 22, which was necessary and sufficient to ameliorate STZ-induced diabetes. Inulin-enriched diets significantly delayed diabetes in NOD mice. Conclusions Fermentable fiber confers microbiota-dependent increases in SCFA and interleukin 22 that, together, may have potential to prevent and/or treat type 1 diabetes., Graphical abstract

Frailty, a specific condition of increased vulnerability and reduced general health associated with aging in older people, is an emerging problem worldwide with major implications for clinical practice and public health. Recent preclinical and clinical studies have supported the safety of mesenchymal stem/stromal cells (MSCs) in the treatment of frailty. Comprehensive study is needed to assess the interrelationship between the condition of frailty and the effects of MSC-based therapy. This randomized controlled phase I/II trial aims to investigate the safety and potential therapeutic efficacy of the allogeneic administration of umbilical cord-derived MSCs (UC-MSCs) in combination with the standard treatment for frailty in Vietnam. Moreover, this study describes the rationales, study designs, methodologies, and analytical strategies currently employed in stem cell research and clinical studies. The primary outcome measures will include the incidences of prespecified administration-associated adverse events and serious adverse events. The potential efficacy will be evaluated based on improvements in frailty conditions (including those determined through a physical examination, patient-reported outcomes, quality of life, immune markers of frailty, metabolism analysis, and cytokine markers from patient plasma). This clinical trial and stem cell analysis associated with patient sampling at different time points aim to identify and characterize the potential effects of UC-MSCs on improving frailty based on the stem cell quality, cytokine/growth factor secretion profiles of UC-MSCs, cellular senescence, and metabolic analysis of patient CD3+ cells providing fundamental knowledge for designing and implementing research strategies in future studies. Clinical Trials Registration Number: NCT04919135

Human bone marrow‐derived mesenchymal stem/stromal cells (BM‐MSCs) represent promising stem cell therapy for the treatment of type 2 diabetes mellitus (T2DM), but the results of autologous BM‐MSC administration in T2DM patients are contradictory. The purpose of this study was to test the hypothesis that autologous BM‐MSC administration in T2DM patient is safe and that the efficacy of the treatment is dependant on the quality of the autologous BM‐MSC population and administration routes. T2DM patients were enrolled, randomly assigned (1:1) by a computer‐based system into the intravenous and dorsal pancreatic arterial groups. The safety was assessed in all the treated patients, and the efficacy was evaluated based on the absolute changes in the hemoglobin A1c, fasting blood glucose, and C‐peptide levels throughout the 12‐month follow‐up. Our data indicated that autologous BM‐MSC administration was well tolerated in 30 T2DM patients. Short‐term therapeutic effects were observed in patients with T2DM duration of, Human bone marrow‐derived mesenchymal stem/stromal cells (BM‐MSCs) represent promising stem cell therapy for the treatment of type 2 diabetes, but the results of autologous BM‐MSC admniistration in T2DM patients are contradicted. Our data indicated that autologous BM‐MSC administration was well tolerated in 30 T2DM patients. The potential therapeutic effects of the treatments were observed in patients with less than 10 years of T2DM and a BMI

Purpose of Review This review aims to provide relevant, aggregate information about a variety of disinfectants and antiseptics, along with potential utility and limitations. While not exhaustive, this review’s goal is to add to the body of literature available on this topic and give interventional providers and practitioners an additional resource to consider when performing procedures. Recent Findings In the current SARS-CoV2 epidemiological environment, infection control and costs associated with healthcare-associated infections (HAIs) are of paramount importance. Even before the onset of SARS-CoV2, HAIs affected nearly 2million patients a year in the USA and resulted in nearly 90,000 deaths, all of which resulted in a cost to hospitals ranging from US$28 billion to 45 billion. The onset SARS-CoV2, though not spread by an airborne route, has heightened infection control protocols in hospitals and, as such, cast a renewed focus on disinfectants and their utility across different settings and organisms. Summary The aim of this review is to provide a comprehensive overview of disinfectants used in the inpatient setting.

BACKGROUND: Gender-incongruent youth may present to gender-affirming medical care (GAMC) later in adolescence and puberty when hormone blockers provide less benefit. Factors influencing age of presentation to GAMC have not been described. METHODS: A sequential mixed methods study. Participants were categorized on the basis of age at presentation to GAMC. Youth presenting at ≥15 years comprised the older-presenting youth, whereas those presenting at RESULTS: Five themes differed between age groups: validity of gender identity, gender journey barriers, influential networks, perceptions of medical therapy, and health care system interactions. Questionnaires were completed by 121 youths and 121 caregivers. Compared with younger-presenting youth, older-presenting youth recognized gender incongruence at older ages, were less likely to have caregivers who helped them access care or LGBTQ+ (lesbian, gay, bisexual, transgender, queer) family members, more often endorsed familial religious affiliations, and experienced greater youth-caregiver disagreement around importance of GAMC. CONCLUSIONS: Family environment appears to be a key determinant of when youth present to GAMC. Whether this association occurs through affecting transgender identity formation and recognition requires further study.

Background Chronic obstructive pulmonary disease (COPD) is currently listed as the 3rd leading cause of death in the United States. COPD is marked by limitations in expiratory airflow, emphysematous destruction of the lungs, bronchitis, and chronic inflammation of the lung tissue. With the emerging prevalence in usage of electronic nicotine delivery systems (ENDS), the impact of ENDS on the development of lung diseases such as COPD requires further attention. Previous studies have shown that β-epithelial Na+ channel (βENaC)- overexpressing mice have multiple emphysematous phenotypes, such as mucus accumulation and chronic inflammation. This study was aimed to elucidate the effects of e-cigarettes, a type of ENDS, on the development of COPD. Methods We hypothesized that acute repetitive usage of ENDS will exacerbate the features of COPD including mucus production, inflammation, and fibrosis, ultimately leading to lung injury. Twenty βENaC mice (10 mice per group) underwent whole body ENDS or sham air exposure for 2 hours daily over 10 days. Bronchoalveolar lavage (BAL) fluid and lung tissues were collected to assess for inflammation, fibrosis, mucus accumulation, and alveolar damage. Results and Discussion Our data showed that ENDS exposure significantly increased the alveolar size as compared with the control. We also found that level of inflammatory cytokines, such as CCL2, IL-13, and IL-10, were elevated in animals exposed to ENDS compared with control. Moreover, we observed ENDS exposure caused mucus accumulation, alveolar destruction, and fibrosis in the bronchioles of the βENaC mice. Additionally, ENDS exposure promoted apoptosis in pulmonary endothelial cell and epithelial cells. Conclusion Our data suggest that nicotine-containing e-cigarettes exacerbates features of COPD involving abnormal lung inflammation, mucus accumulation and apoptosis in βEnaC mice.

The Pediatric Emergency Care Applied Research Network (PECARN) Head Injury/Trauma Algorithm is a well-validated decision rule used to identify patients at low risk of clinically important traumatic brain injuries who may not need head CT. In adult patients with mild head trauma, elevated serum glucose and white cell count (WCC) have been associated with abnormal head CT findings. Currently, glucose or WCC is not considered in pediatric patients. The objective of this study was to determine if elevations in glucose or WCC could be used as additional tools to risk-stratify pediatric trauma patients for intracranial injury (ICI). Data were abstracted from the Maryland Trauma Registry and from electronic medical records for patients at the Johns Hopkins Children's Center from 2017 to 2020. We evaluated 145 encounters that met the inclusion criteria. There were 33 cases of ICI on CT. In addition to higher median glucose and WCC, we found that patients with ICI had a younger median age and were less likely to have other clinically significant injuries than patients without ICI. Following multiple logistic regression analysis, WCC (OR 1.113, 95% CI 1.02 to 1.21), younger age (OR 0.89, 95% CI 0.8 to 0.98), and absence of other injuries (OR 0.41, 95% CI 0.23 to 0.73) were found to be associated with risk of ICI. The area under the curve for our model was 0.79. When used with the PECARN algorithm, our model could help determine which patients may avoid head CT or undergo a shorter observation period.

Background Comparing outcomes of care between public and private hospitals is critical to inform patients and improve care quality. Purpose To compare complication rates following catheter ablation of atrial fibrillation (AF) up to 30-days post discharge between public and private hospitals. Methods We included patients ≥18 years who underwent AF ablation in the Australian states of New South Wales, Queensland, Victoria, and Western Australia from 2010–2015. The primary outcome was the occurrence of any complication up to 30-days after discharge. The association between provider type and the risk of complications was examined using logistic regression with inverse probability of treatment weighting (IPTW) propensity scores to account for differences in measured confounders. The minimum strength of association required for an unmeasured confounder to nullify any observed association was estimated using the E value. Results We identified 18,074 AF ablations during the study period (mean age 62.3±11.4y, 28.8% female, 78.4% performed in private hospitals). Patients ablated at public hospitals were younger (59.3 vs. 63.1y, p Conclusion AF ablation at a public hospital was associated with a 46% higher risk of complications compared with ablation at a private hospital, mainly driven by a higher risk of complications requiring cardiac surgery, acute kidney injury, cardiorespiratory failure, infections, and bleeding. The disparity could be due to differences in care quality between two sectors or explained by unmeasured confounders such as higher procedural complexity in public hospitals. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): The National Heart Foundation of Australia

Background Recent studies from the United States report rising rates of in-hospital complications and mortality following catheter ablation of atrial fibrillation (AF) but whether such a trend is observed in other populations is uncertain. Purpose To examine the trends in complications and mortality following AF ablations up to 30 days after discharge in Australia and New Zealand (ANZ) using nationwide data. Methods All patients ≥18y undergoing catheter ablation of AF from 2010–2015 were identified using hospitalisation data from all public and most private hospitals in ANZ. The primary endpoint was one or more procedural complications during the hospital stay or within 30 days of discharge. The secondary endpoints were mortality and other specific complications. Unadjusted trend was evaluated using Cochran-Armitage test while that of complications, adjusting for differences in other characteristics, was evaluated using multivariate logistic regression with the year of ablation modelled as a continuous variable. Results are reported as odd ratios (OR) and 95% confidence intervals (CI). Results A total of 22,582 AF ablations were included (mean age 62.2±11.6y, 29.1% female, 94.4% elective procedures). The number of ablations increased by 26.4% during the study period (3,097 in 2010 to 3,915 in 2015). Rates of heart failure (8.98% to 10.09%, p for trend=0.010), diabetes (4.52% to 12.46%, p Conclusions Though more patients with heart failure, diabetes and chronic kidney disease underwent catheter ablation of AF over time in ANZ, the overall complication rate was unchanged with a significant decrease in the incidences of major bleeding and venous thromboembolism. However, rate of acute kidney injury nearly doubled, and this could be a potential target for efforts to further improve procedural safety. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): The National Heart Foundation of Australia

OBJECTIVES: To investigate the associations of household mold and pesticide use with risk of childhood asthma and examine the potential effect modification by child’s sex at a national level in the U.S. METHODS: Nationally representative data were drawn from the cross-sectional 2017 and 2018 National Surveys of Children’s Health. Household mold and pesticide exposures during the past 12 months and physician-diagnosed childhood asthma were assessed by standard questionnaires administered to primary caregivers. Multivariable logistic regression models were used to calculate adjusted odds ratios (aOR) for current asthma, adjusting for child, caregiver, and household covariates. We also examined potential effect modification by child’s sex. Sampling weights accounted for the complex survey design. RESULTS: Among 41,423 U.S. children in 2017–2018, the weighted prevalence of current asthma was 10.8% in household mold-exposed children, compared with 7.2% in non-exposed children (P

In this review, we evaluate recent literature on use of ER granisetron in clinical practice as compared with current antiemetics and describe its potential uses for perioperative PONV prophylaxis and treatment. Recent literature was evaluated on ER granisetron use compared with currently used antiemetic agents ondansetron, droperidol, metoclopramide, promethazine, and dexamethasone with a focus on procedural anti-emesis. Though promising great effect, application of extended release granisetron to clinical use may be limited by it's increased relative cost.

This cohort study identifies characteristics of mental health patients boarding for longer than 24 hours in a pediatric emergency department.

OBJECTIVE: To investigate if 20 cc buffered 1% lidocaine paracervical block decreases pain during intrauterine device (IUD) placement. METHODS: In a randomized, single-blind, placebo-controlled trial, women were assigned to receive either 20 cc buffered 1% lidocaine paracervical block or no block prior to IUD placement. The primary outcome was pain with IUD placement measured on a 100 mm visual analog score (VAS). Our sample size had 80% power (α=0.05) to detect a 20 mm difference in VAS scores with a standard deviation of 28 mm. Secondary outcomes included pain with speculum placement, paracervical-block administration, tenaculum placement, 5 minutes post-procedure, and overall pain perception. RESULTS: From October 7, 2014, through October 26, 2017, 64 women were enrolled and analyzed (33 in paracervical-block arm, 31 in no-block arm). There were no differences in baseline demographics between the groups. Women who received the paracervical block reported less pain with IUD placement compared to women who received no block (median VAS score of 33 mm compared with 54 mm, p=0.002). Pain was significantly less in the intervention group for uterine sounding (30 mm compared with 47 mm, p=0.005), 5 minutes after placement (12 mm compared with 27 mm, p=0.005) and overall pain perception (30 mm compared with 51 mm, p=0.015). Participants who received the paracervical block experienced more pain with block administration compared to placebo (30 mm compared with 8 mm, p=0.003). There was no perceived-pain difference for speculum insertion (10 mm compared with 6 mm, p=0.447) or tenaculum placement (15 mm compared with 10 mm, p=0.268). CONCLUSION: A 20 cc buffered 1% lidocaine paracervical block decreases pain with IUD placement (primary outcome), uterine sounding (secondary outcome), and 5 minutes after placement (secondary outcome). While paracervical block administration can be painful, perception of pain for overall IUD placement procedure is lower compared to no block.

BACKGROUND In the United States, up to 57% of women report resumption of sexual activity by the 6 week postpartum visit. Effective contraception should be addressed and provided at that time, to avoid unintended pregnancies and optimize interpregnancy intervals. Long-acting reversible contraceptives are the most effective forms of reversible contraception and are increasingly popular during the postpartum period. However, timing of postpartum intrauterine device (IUD) placement varies among providers and many delay insertion due to concerns for uterine perforation or expulsion of the IUD. OBJECTIVE This study aimed to evaluate uterine perforation and expulsion rates with IUD insertion at 4-8 weeks postpartum vs 9-36 weeks postpartum. STUDY DESIGN We performed a retrospective cohort study using the Kaiser Permanente Southern California electronic medical record from 2010 to 2016. We calculated the proportion of perforations and expulsions with IUD insertion at 4-8 weeks vs 9-36 weeks postpartum. Our primary outcome was the perforation rate. Secondarily, we evaluated the expulsion rate. For our minimum sample size calculation, to detect a difference of 0.5% in the perforation rate, with a baseline perforation rate of 0.5% for the 9-36 week postpartum IUD placement group, 80% power, and 5% alpha error rate, we would need at least 4221 participants per group, 8442 in total. RESULTS A total of 24,959 patients met inclusion criteria (n=13,180 in the 4-8 week group, n=11,777 in the 9-36 week group). Of 430 patients with a confirmed complication, 157 uterine perforations and 273 IUD expulsions were identified. Perforation rates were significantly higher with placement at 4-8 weeks than at 9-36 weeks (0.78% vs 0.46%; P=.001). After adjusting for race and ethnicity, breastfeeding, IUD type, provider type, parity, most recent delivery, and body mass index, the odds of perforation remained higher with placement at 4-8 weeks than at 9-36 weeks (adjusted odds ratio, 1.92; 95% confidence interval, 1.28-2.89). Our Kaplan-Meier survival curve showed that the risk of uterine perforation remained elevated until approximately 22-23 weeks postpartum. Expulsion rates were similar between the 2 groups (1.02 vs 1.17; P=.52). CONCLUSION Uterine perforation after interval postpartum IUD insertion is greater at 4-8 weeks than at 9-36 weeks, although perforation rates remain low at

Lactic acid bacteria (LAB) are the common probiotics. Here, we investigated the antiviral protective effects of heat-killed LAB strain Lactobacillus casei DK128 (DK128) on influenza viruses. Intranasal treatment of mice with DK128 conferred protection against different subtypes of influenza viruses by lessening weight loss and lowering viral loads. Protection via heat-killed DK128 was correlated with an increase in alveolar macrophage cells in the lungs and airways, early induction of virus specific antibodies, reduced levels of pro-inflammatory cytokines and innate immune cells. Importantly, the mice that were protected against primary viral infection as a result of heat-killed DK128 pretreatment developed subsequent heterosubtypic immunity against secondary virus infection. For protection against influenza virus via heat-killed DK128 pretreatment, B cells and partially CD4 T cells but not CD8 T cells were required as inferred from studies using knockout mouse models. Our study provides insight into how hosts can be equipped with innate and adaptive immunity via heat-killed DK128 treatment to protect against influenza virus, supporting that heat-killed LAB may be developed as anti-virus probiotics.

Regulatory and effector T helper (Th) cells are abundant at mucosal surfaces, especially in the intestine, where they control the critical balance between tolerance and inflammation. However, the key factors that reciprocally dictate differentiation along these specific lineages remain incompletely understood. Here we report that the interleukin-1 (IL-1) family member IL-36γ signals through IL-36 receptor, myeloid differentiation primary response gene 88, and nuclear factor-κBp50 in CD4+ T cells to potently inhibit Foxp3-expressing induced regulatory T cell (Treg) development, while concomitantly promoting the differentiation of Th9 cells via a IL-2-STAT5- (signal transducer and activator of transcription factor 5) and IL-4-STAT6-dependent pathway. Consistent with these findings, mice deficient in IL-36γ were protected from Th cell-driven intestinal inflammation and exhibited increased colonic Treg cells and diminished Th9 cells. Our findings thus reveal a fundamental contribution for the IL-36/IL-36R axis in regulating the Treg-Th9 cell balance with broad implications for Th cell-mediated disorders, such as inflammatory bowel diseases and particularly ulcerative colitis.

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The human gut microbiome partakes in a bidirectional communication pathway with the central nervous system (CNS), named the microbiota-gut-brain axis. The microbiota-gut-brain axis is believed to modulate various central processes through the vagus nerve as well as production of microbial metabolites and immune mediators which trigger changes in neurotransmission, neuroinflammation, and behavior. Little is understood about the utilization of microbiome manipulation to treat disease. Though studies exploring the role of the microbiome in various disease processes have shown promise, mechanisms remain unclear and evidence-based treatments for most illnesses have not yet been developed. The animal studies reviewed here offer an excellent array of basic science research that continues to clarify mechanisms by which the microbiome may affect mental health. More evidence is needed, particularly as it relates to translating this work to human subjects. The studies presented in this paper largely demonstrate encouraging results in the treatment of depression. Limitations include small sample sizes and heterogeneous methodology. The exact mechanism by which the gut microbiota causes or alters neuropsychiatric disease states is not fully understood. In this review, we focus on recent studies investigating the relationship between gut microbiome dysbiosis and the pathogenesis of depression. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Background Adolescents with low self-esteem often experience internalizing psychopathology (i.e., anxiety, depression). Self-esteem may therefore be a clinically relevant construct for assessment and treatment outcomes. We examined whether general and domain-specific (family, peer, academic) self-esteem are related to adolescents’ internalizing symptom severity and response to cognitive behavioural therapy (CBT). Method Participants were 89 adolescents ages 14 to 18 years (M = 16.3, 70% females) from an outpatient clinic who were referred for CBT. Adolescents completed measures of self-esteem at baseline and measures of internalizing symptoms at baseline and at the end of a manualized group CBT intervention. Results Lower peer and family self-esteem, but not academic self-esteem, were associated with more internalizing symptoms at baseline, after controlling for general self-esteem. However, only higher general self-esteem, and not any of the specific self-esteem domains, predicted lower internalizing symptoms at posttreatment. Follow-up analyses revealed differential associations between family and peer self-esteem domains and anxious and depressive symptoms. Limitations Only self-report measures were used. The relatively small sample size may have limited power to detect small effects. Conclusions Self-esteem in domains regarding family and peer relationships may be important in the evaluation of adolescents with internalizing problems. Adolescents with low general self-esteem may benefit less from CBT than other adolescents. Addressing negative self-perceptions may be necessary to reduce internalizing symptoms for adolescents with low self-esteem.

Background It is important to investigate complications of catheter ablation for atrial fibrillation (AF) - an increasingly common procedure - to inform patients and guide efforts to improve procedural quality. However, clinical trials and registries are limited by selection bias, while existing population-based studies either lack nation-wide data, or fail to report post-discharge complications. The timing and impact of these complications are also poorly understood. Purpose To obtain unbiased and comprehensive estimates of complications of AF ablations using national data from Australia and New Zealand. We also evaluated the impact of in-hospital complications on the length of stay and assessed the timing of post-discharge complications. Methods We included patients aged ≥18 years undergoing catheter ablation with a primary diagnosis of AF between 2010–2015 in all public and most private hospitals in Australia and New Zealand. The primary outcome was the occurrence of major complications in-hospital or up to 30-days after discharge. We identified major complications based on a literature review and expert clinical opinion and defined these using International Classification of Diseases – 10th revision, Australian Modification diagnoses codes and Australian Classification of Health Interventions procedure codes. We determined the impact of in-hospital complications on the length of stay, adjusting for other covariates, by using negative binomial regression, and reported results as incident rate ratio (IRR) and 95% confidence intervals (CI). Time to first post-discharge complication was evaluated using Kaplan Meier survival analysis. Results A total of 20,057 AF ablations were included (mean age 62.1±11.6 y, 56.7% ≤65 years old; 29.2% female; median length of stay 1 day). Of these, major complications occurred in 6.3% procedures (4.6% occurring in-hospital and a further 2.0% occurring in the 30-day post discharge). The most common complications were bleeding or haematoma formation and perforation (primarily pericardial effusion), which accounted to 60.3% and 14.3% of all complications, respectively. Rate of procedure-related deaths was 0.1%. Occurrence of an in-hospital complication more than doubled the length of stay (IRR: 2.3, 95% CI 2.2–2.4) with complications requiring cardiac surgery (IRR 4.5, 95% CI 3.2–6.4) and vascular injuries (IRR 3.9, 95% CI 3.1–4.9) having the length of stay prolonged the most (Figure 1A). In the first-week, 67.3% of post-discharge complications had occurred, and this number reached 95% within three-weeks (Figure 1B). Conclusions Major complications after AF ablation were common. In-hospital complications doubled the length of stay. Approximately 30% of complications occurred after discharge with the risk highest in the first seven days. Efforts to reduce complications should focus on reducing the incidence of bleeding and pericardial effusions which counted for more than 75% of all complications. Acknowledgement/Funding National Heart Foundation of Australia, The Hospital Research Foundation

Interleukin (IL)-2 is expressed during T cell activation and induces the proliferation and differentiation of T cells. CD4+Foxp3+ regulatory T cells (Tregs) constitutively express the high affinity IL-2 receptor (CD25/IL-2Rα) and rapidly respond to IL-2 to elaborate numerous suppressive mechanisms that limit immune-mediated pathologies. Accumulating evidence supports the concept that an aberrant balance between Tregs and Teff contribute to the pathology of intestinal inflammation and that the IL-2/Treg axis is a potential pathway to exploit for the treatment of inflammatory bowel disease (IBD). Here, we show that treatment of mice with IL-2/IL-2 antibody (JES6-1) immunocomplex during DSS-induced colitis induced Foxp3+ Treg expansion, but also potently stimulated GATA3+ type 2 innate lymphoid cell (ILC2) proliferation and high-level expression of IL-5. Furthermore, IL-2/JES6-1 treatment resulted in massive eosinophil accumulation and activation in the inflamed colon, and afforded only modest protection from colitis. In light of these findings, we observed that combined IL-2/JES6-1 and anti-IL-5 mAb treatment was most effective at ameliorating DSS-induced colitis compared to either treatment alone and that this regimen allowed for Foxp3+ Treg expansion without concomitant eosinophilia. Collectively, our findings provide insight into how blockade of IL-5 may aid in optimizing IL-2 immunotherapy for the treatment of intestinal inflammation.

Novel phenolic branched-chain fatty acids (PBC-FAs) were evaluated for their antimicrobial properties against both gram-positive ( Listeria innocua , Bacillus subtilis , Enterococcus faecium ) and gram-negative ( Escherichia coli , Salmonella Typhimurium, and Pseudomonas tolaasii ) bacteria. In addition, PBC-FA derivatives, such as PBC-FA methyl ester mixture, methyl-branched fatty acid mixtures, and trimethylsilyl-PBC-FA methyl esters, were synthesized to study the structure activity relationship. Results showed that PBC-FAs were a potent antimicrobial against gram-positive bacteria with MICs of 1.8 to 3.6 μg/ml. The compounds were less effective against gram-negative bacteria. Derivatives of PBC-FAs and an equimolar mixture of oleic acid and phenol all had MICs above 233 μg/ml against both gram-positive and gram-negative bacteria. Comparison of antimicrobial activities of the PBC-FAs with those of the derivatives suggests that the carboxylic group in the fatty acid moiety and the hydroxyl group on the phenol moiety were responsible for the antimicrobial efficacy. Growth curves of L. innocua revealed that PBC-FAs prevented bacterial growth, while MBC-FAs only delayed the onset of rapid growth of L. innocua . Our results demonstrated that the novel PBC-FAs have potential for use as antimicrobials against gram-positive bacteria.

Recognizing the clinical presentation of a child with abusive injuries is crucial. This review article gives an updated summary on inflicted intraoral, esophageal, and abdominal visceral injuries, including current recommendations on recognition, evaluation, screening value, and management of at risk children. Physical abuse should be suspected in precruising infants with intraoral injuries. When sexual abuse is suspected, referral to specialized centers equipped to conduct comprehensive examination and forensic testing by an experienced provider adhering to chain of evidence protocol is recommended. Abdominal trauma is the second most common cause of death in children who have been abused. The diagnosis and management of these injuries require careful consideration. Routine screening hepatic transaminases should be guided by the age of child and clinical scenario. A definitive confirmatory computed tomography scan of the abdomen and pelvis should be performed for those with transaminase levels more than 80 IU/L, or in all concerning cases with history and examination consistent with abusive abdominal trauma.

The Interventional Pain Management Ladder reflects a possible paradigm disruption in chronic pain management. For treatment of chronic pain after failure of pharmacotherapy, the standard of care should shift to less-invasive interventional pain management as the preferred second-line treatment prior to more tissue-disruptive spine surgery. Spinal cord stimulation with neuromodulation is an effective, reversible, and minimally invasive interventional therapy for many types of chronic and difficult-to-treat pain. This chapter presents a modern approach of least invasive therapies first prior to more tissue disruptive measures and aligns chronic pain care with treatment of other serious medical conditions, such as heart attack and stroke.

Objective To evaluate intramuscular ketorolac compared with placebo saline injection for pain control with intrauterine device (IUD) placement. Methods We conducted a randomized, double-blind, placebo-controlled trial between July 2012 and March 2014. Patients received 30 mg ketorolac or placebo saline intramuscular injection 30 minutes before IUD placement. The primary outcome was pain with IUD placement on a 10-cm visual analog scale. Sample size was calculated to provide 80% power to show a 2.0-cm difference (α=0.05) in the primary outcome. Secondary outcomes included pain with study drug injection, speculum insertion, tenaculum placement, uterine sounding, and at 5 and 15 minutes after IUD placement. Results A total of 67 women participated in the study, 33 in the ketorolac arm and 34 in the placebo arm. There were no differences in baseline demographics including age, body mass index, and race. There were no differences in median pain scores for IUD placement in the placebo compared with ketorolac groups (5.2 compared with 3.6 cm, P=.99). There was a decrease in median pain scores at 5 minutes (2.2 compared with 0.3 cm, P≤.001) and 15 minutes (1.6 compared with 0.1 cm, P≤.001) after IUD placement but no difference for all other time points. Nulliparous participants (n=16, eight per arm) had a decrease in pain scores with IUD placement (8.1 compared with 5.4 cm, P=.02). In this study, 22% of participants in the placebo group and 18% in the ketorolac group reported injection pain was as painful as IUD placement. Conclusion Ketorolac does not reduce pain with IUD placement but does reduce pain at 5 and 15 minutes after placement. Clinical trial registration ClinicalTrials.gov; www.clinicaltrials.gov, NCT01664559. Level of evidence I.

Background In 2009 the I-PASS Study Group was formed by patient safety, medical education, health services research, and clinical experts from multiple institutions in the United States and Canada. When the I-PASS Handoff Program, which was developed by the I-PASS Study Group, was implemented in nine hospitals, it was associated with a 30% reduction in injuries due to medical errors and significant improvements in handoff processes, without any adverse effects on provider work flow. Methods To effectively disseminate and adapt I-PASS for use across specialties and disciplines, a series of federally and privately funded dissemination and implementation projects were carried out following the publication of the initial study. The results of these efforts have informed ongoing initiatives intended to continue adapting and scaling the program. Results As of this writing, I-PASS Study Group members have directly worked with more than 50 hospitals to facilitate implementation of I-PASS. To further disseminate I-PASS, Study Group members delivered hundreds of academic presentations, including plenaries at scientific meetings, workshops, and institutional Grand Rounds. Some 3,563 individuals, representing more than 500 institutions in the 50 states in the United States, the District of Columbia, Puerto Rico, and 57 other countries, have requested access to I-PASS materials. Most recently, the I-PASSSM Patient Safety Institute has developed a virtual immersion training platform, mobile handoff observational tools, and processes to facilitate further spread of I-PASS. Conclusion Implementation of I-PASS has been associated with substantial improvements in patient safety and can be applied to a variety of disciplines and types of patient handoffs. Widespread implementation of I-PASS has the potential to substantially improve patient safety in the United States and beyond.