An immunohistochemical atlas of necroptotic pathway expression.

Necroptosis is a lytic form of regulated cell death reported to contribute to inflammatory diseases of the gut, skin and lung, as well as ischemic-reperfusion injuries of the kidney, heart and brain. However, precise identification of the cells and tissues that undergo necroptotic cell death in vivo has proven challenging in the absence of robust protocols for immunohistochemical detection. Here, we provide automated immunohistochemistry protocols to detect core necroptosis regulators - Caspase-8, RIPK1, RIPK3 and MLKL - in formalin-fixed mouse and human tissues. We observed surprising heterogeneity in protein expression within tissues, whereby short-lived immune barrier cells were replete with necroptotic effectors, whereas long-lived cells lacked RIPK3 or MLKL expression. Local changes in the expression of necroptotic effectors occurred in response to insults such as inflammation, dysbiosis or immune challenge, consistent with necroptosis being dysregulated in disease contexts. These methods will facilitate the precise localisation and evaluation of necroptotic signaling in vivo.

Does gender moderate resiliency variables and posttraumatic stress symptoms in informal caregivers of neurocritical care patients? An exploratory study.

We examined gender differences between resiliency factors (i.e. mindfulness, self-efficacy, coping, intimate care, and caregiver preparedness) and posttraumatic stress symptoms (PTSS) in informal caregivers of patients in the neuroscience intensive care unit (Neuro-ICU). Ninety-two informal caregivers were enrolled during patients' hospitalization and completed resiliency measures at baseline, and a PTSS measure at baseline, 3 and 6 months. We conducted five ANCOVAs to explore gender and resiliency on PTSS. No significant main effects of gender on PTSS were observed across time points. However, main effects were seen for resiliency on PTSS at baseline for informal caregivers with high (vs. low) mindfulness, coping, and self-efficacy. Gender moderated the association between mindfulness and PTSS (i.e. high mindfulness at baseline was associated with lower PTSS in males compared to females at 3 months) and intimate care and PTSS (high intimate care at baseline was associated with lower PTSS in males than females at 6 months; high intimate care at baseline for females was associated with lower PTSS at 6 months than females with low intimate care). Overall, we observed associations among informal caregivers' gender, resiliency, and PTSS, with males particularly benefitting from mindfulness and intimate care. These findings hold value for future inquiry into gender differences in this population with possible clinical implications.

Generating a multimodal artificial intelligence model to differentiate benign and malignant follicular neoplasms of the thyroid: A proof-of-concept study.

BACKGROUND: Machine learning has been increasingly used to develop algorithms that can improve medical diagnostics and prognostication and has shown promise in improving the classification of thyroid ultrasound images. This proof-of-concept study aims to develop a multimodal machine-learning model to classify follicular carcinoma from adenoma. METHODS: This is a retrospective study of patients with follicular adenoma or carcinoma at a single institution between 2010 and 2022. Demographics, imaging, and perioperative variables were collected. The region of interest was annotated on ultrasound and used to perform radiomics analysis. Imaging features and clinical variables were then used to create a random forest classifier to predict malignancy. Leave-one-out cross-validation was conducted to evaluate classifier performance using the area under the receiver operating characteristic curve. RESULTS: Patients with follicular adenomas (n = 7) and carcinomas (n = 11) with complete imaging and perioperative data were included. A total of 910 features were extracted from each image. The t-distributed stochastic neighbor embedding method reduced the dimension to 2 primary represented components. The random forest classifier achieved an area under the receiver operating characteristic curve of 0.76 (clinical only), 0.29 (image only), and 0.79 (multimodal data). CONCLUSION: Our multimodal machine learning model demonstrates promising results in classifying follicular carcinoma from adenoma. This approach can potentially be applied in future studies to generate models for preoperative differentiation of follicular thyroid neoplasms.

Treatment options and emotional well-being in patients with rosacea: An unsupervised machine learning analysis of over 200,000 posts.

Background: Many patients with rosacea join online support groups to gather and disseminate information about disease management and provide emotional support for others. Objective: To better understand rosacea patient's primary concerns for the disease as well as their disease search patterns online. Methods: Overall, 207,038 posts by 41,400 users were collected from June 1, 2017, to June 1, 2022, in a popular online forum. We applied Latent Dirichlet Allocation (LDA), an unsupervised machine learning model, to organize the posts into topics. Keywords for each topic supplied by LDA were used to manually assign topic and category labels. Results: Twenty-three significant topics of conversation were identified and organized into 4 major categories, including Management (50.33%), Clinical Presentation (24.14%), Emotion (21.97%), and Information Appraisal (3.57%). Limitations: Although we analyzed the largest forum on the internet for rosacea, generalizability is limited given the presence of other smaller forums and the skewed demographics of forum users. Conclusion: Social media forums play an important role for disease discussion and emotional venting. Although rosacea management was the most frequently discussed topic, emotional posting was a significantly prevalent occurrence.

Pseudouridine guides germline small RNA transport and epigenetic inheritance.

Epigenetic modifications that arise during plant and animal development, such as DNA and histone modification, are mostly reset during gamete formation, but some are inherited from the germline including those marking imprinted genes1. Small RNAs guide these epigenetic modifications, and some are also inherited by the next generation2,3. In C. elegans, these inherited small RNAs have poly (UG) tails4, but how inherited small RNAs are distinguished in other animals and plants is unknown. Pseudouridine (Ψ) is the most abundant RNA modification but has not been explored in small RNAs. Here, we develop novel assays to detect Ψ in short RNA sequences, demonstrating its presence in mouse and Arabidopsis microRNAs and their precursors. We also detect substantial enrichment in germline small RNAs, namely epigenetically activated siRNAs (easiRNAs) in Arabidopsis pollen, and piwi-interacting piRNAs in mouse testis. In pollen, pseudouridylated easiRNAs are localized to sperm cells, and we found that PAUSED/HEN5 (PSD), the plant homolog of Exportin-t, interacts genetically with Ψ and is required for transport of easiRNAs into sperm cells from the vegetative nucleus. We further show that Exportin-t is required for the triploid block: chromosome dosage-dependent seed lethality that is epigenetically inherited from pollen. Thus, Ψ has a conserved role in marking inherited small RNAs in the germline.

The Effect of 2019 Coronavirus Stay-at-Home Order on Geriatric Trauma Patients in Southern California.

BACKGROUND: California issued stay-at-home (SAH) orders to mitigate COVID-19 spread. Previous studies demonstrated a shift in mechanisms of injuries (MOIs) and decreased length of stay (LOS) for the general trauma population after SAH orders. This study aimed to evaluate the effects of SAH orders on geriatric trauma patients (GTPs), hypothesizing decreased motor vehicle collisions (MVCs) and LOS. METHODS: A post-hoc analysis of GTPs (≥65 years old) from 11 level-I/II trauma centers was performed, stratifying patients into 3 groups: before SAH (1/1/2020-3/18/2020) (PRE), after SAH (3/19/2020-6/30/2020) (POST), and a historical control (3/19/2019-6/30/2019) (CONTROL). Bivariate comparisons were performed. RESULTS: 5486 GTPs were included (PRE-1756; POST-1706; CONTROL-2024). POST had a decreased rate of MVCs (7.6% vs 10.6%, P = .001; vs 11.9%, P < .001) and pedestrian struck (3.4% vs 5.8%, P = .001; vs 5.2%, P = .006) compared with PRE and CONTROL. Other mechanisms of injury, LOS, mortality, and operations performed were similar between cohorts. However, POST had a lower rate of discharge to skilled nursing facility (SNF) (20% vs 24.5%, P = .001; and 20% vs 24.4%, P = .001). CONCLUSION: This retrospective multicenter study demonstrated lower rates of MVCs and pedestrian struck for GTPs, which may be explained by decreased population movement as a result of SAH orders. Contrary to previous studies on the generalized adult population, no differences in other MOIs and LOS were observed after SAH orders. However, there was a lower rate of discharge to SNF, which may be related to a lack of resources due to the COVID-19 pandemic, and thus potentially negatively impacted recovery of GTPs.Keywords.

FOXM1-CD44 Signaling Is Critical for the Acquisition of Regorafenib Resistance in Human Liver Cancer Cells.

Regorafenib is a multikinase inhibitor that was approved by the US Food and Drug administration in 2017. Cancer stem cells (CSCs) are a small subset of cancer-initiating cells that are thought to contribute to therapeutic resistance. The forkhead box protein M1 (FOXM1) plays an important role in the regulation of the stemness of CSCs and mediates resistance to chemotherapy. However, the relationship between FOXM1 and regorafenib resistance in liver cancer cells remains unknown. We found that regorafenib-resistant HepG2 clones overexpressed FOXM1 and various markers of CSCs. Patients with hepatocellular carcinoma also exhibited an upregulation of FOXM1 and resistance to regorafenib, which were correlated with a poor survival rate. We identified a close relationship between FOXM1 expression and regorafenib resistance, which was correlated with the survival of patients with hepatocellular carcinoma. Thus, a strategy that antagonizes FOXM1-CD44 signaling would enhance the therapeutic efficacy of regorafenib in these patients.

Adolescent Trauma During the COVID Pandemic: Just Like Adults, Children, or Someone Else?

COVID-19 stay-at-home (SAH) orders were impactful on adolescence, when social interactions affect development. This has the potential to change adolescent trauma. A post-hoc multicenter retrospective analysis of adolescent (13-17 years-old) trauma patients (ATPs) at 11 trauma centers was performed. Patients were divided into 3 groups based on injury date: historical control (CONTROL:3/19/2019-6/30/2019, before SAH (PRE:1/1/2020-3/18/2020), and after SAH (POST:3/19/2020-6/30/2020). The POST group was compared to both PRE and CONTROL groups in separate analyses. 726 ATPs were identified across the 3 time periods. POST had a similar penetrating trauma rate compared to both PRE (15.8% vs 13.8%, P = .56) and CONTROL (15.8% vs 14.5%, P = .69). POST also had a similar rate of suicide attempts compared to both PRE (1.2% vs 1.5%, P = .83) and CONTROL (1.2% vs 2.1%, P = .43). However, POST had a higher rate of drug positivity compared to CONTROL (28.6% vs 20.6%, P = .032), but was similar in all other comparisons of alcohol and drugs to PRE and POST periods (all P > .05). Hence ATPs were affected differently than adults and children, as they had a similar rate of penetrating trauma, suicide attempts, and alcohol positivity after SAH orders. However, they had increased drug positivity compared to the CONTROL, but not PRE group.

Decreased hospital length of stay and intensive care unit admissions for non-COVID blunt trauma patients during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic overwhelmed hospitals, forcing adjustments including discharging patients earlier and limiting intensive care unit (ICU) utilization. This study aimed to evaluate ICU admissions and length of stay (LOS) for blunt trauma patients (BTPs). METHODS: A retrospective review of COVID (3/19/20-6/30/20) versus pre-COVID (3/19/19-6/30/19) BTPs at eleven trauma centers was performed. Multivariable analysis was used to identify risk factors for ICU admission. RESULTS: 12,744 BTPs were included (6942 pre-COVID vs. 5802 COVID). The COVID cohort had decreased mean LOS (3.9 vs. 4.4 days, p = 0.029), ICU LOS (0.9 vs. 1.1 days, p < 0.001), and rate of ICU admission (22.3% vs. 24.9%, p = 0.001) with no increase in complications or mortality compared to the pre-COVID cohort (all p > 0.05). On multivariable analysis, the COVID period was associated with decreased risk of ICU admission (OR = 0.82, CI 0.75-0.90, p < 0.001). CONCLUSIONS: BTPs had decreased LOS and associated risk of ICU admission during COVID, with no corresponding increase in complications or mortality.

Health Behaviors During the COVID-19 Epidemic: Perspectives From Studying International Coping and Compliance.

Control of the COVID-19 pandemic requires significant changes in people's health behaviors. We offer this multidisciplinary perspective on the extent of compliance with social distancing recommendations and on coping with these measures around the globe in the first months of the pandemic. We present descriptive data from our survey of 17,650 respondents across 18 countries and territories in June 2020. The majority of respondents worried about contracting the virus. Nearly all engaged in at least some preventive behaviors, particularly handwashing, mask wearing, and avoiding social events. Most reported that it would be difficult to continue these behaviors for more than a few months, and about half reported feeling more anxious since the start of the pandemic. Commonly reported coping behaviors included news consumption, watching television, and sleeping. Our cross-national study highlights areas for developing and implementing health behavior interventions in the global fight to stop the spread of COVID-19.

Effects of the COVID-19 pandemic on pediatric trauma in Southern California.

PURPOSE: The COVID-19 pandemic resulted in increased penetrating trauma and decreased length of stay (LOS) amongst the adult trauma population, findings important for resource allocation. Studies regarding the pediatric trauma population are sparse and mostly single-center. This multicenter study examined pediatric trauma patients, hypothesizing increased penetrating trauma and decreased LOS after the 3/19/2020 stay-at-home (SAH) orders. METHODS: A multicenter retrospective analysis of trauma patients ≤ 17 years old presenting to 11 centers in California was performed. Demographic data, injury characteristics, and outcomes were collected. Patients were divided into three groups based on injury date: 3/19/2019-6/30/2019 (CONTROL), 1/1/2020-3/18/2020 (PRE), 3/19/2020-6/30/2020 (POST). POST was compared to PRE and CONTROL in separate analyses. RESULTS: 1677 patients were identified across all time periods (CONTROL: 631, PRE: 479, POST: 567). POST penetrating trauma rates were not significantly different compared to both PRE (11.3 vs. 9.0%, p = 0.219) and CONTROL (11.3 vs. 8.2%, p = 0.075), respectively. POST had a shorter mean LOS compared to PRE (2.4 vs. 3.3 days, p = 0.002) and CONTROL (2.4 vs. 3.4 days, p = 0.002). POST was also not significantly different than either group regarding intensive care unit (ICU) LOS, ventilator days, and mortality (all p > 0.05). CONCLUSIONS: This multicenter retrospective study demonstrated no difference in penetrating trauma rates among pediatric patients after SAH orders but did identify a shorter LOS.

The association between oral health status and the clinical outcome of cirrhotic patients on the waiting list for liver transplantation.

Liver transplantation (LT) candidates often present with poor oral hygiene, which could potentially lead to systemic infections and sepsis owing to their cirrhotic state. In this study, we investigated the oral health status of LT candidates and propose guidance for the detection and treatment of encountered oral lesions among these patients. The decayed, missing, and filled teeth (DMFT) index was determined through oral examination. The presence of dental calculus was detected using panoramic radiography and defined by the radiopaque dental calculus (RDC). From January 2011 to August 2018, 56 LT candidates were enrolled with a median follow-up of 39 months. The overall mean numbers of decayed, missing, and filled teeth among these patients were 2.7 ± 2.8, 10.9 ± 8.3, and 5.4 ± 4.5, respectively. Eighteen patients (32.1%) had RDC. The 5-year survival rates of all 56 patients was 57.7%, while that of those who either received LT (23 patients) or not were 82.1% and 39.8%, respectively. A Cox regression model revealed better overall survival of patients after LT (adjusted hazard ratio [aHR] = 0.067, p = 0.001), worse survival among patients with RDC (aHR = 3.468, p = 0.010), at Child-Pugh stages B and C (aHR for stage B = 11.889, p = 0.028; aHR for stage C = 19.257, p = 0.013) compared to patients at Child-Pugh stage A, and those with a model for end-stage liver disease (MELD) score ≥25 (aHR = 13.721, p = 0.018). This study demonstrates that RDC was associated with worse prognosis in LT candidates. We therefore recommend that interprofessional collaboration should be a routine preoperative procedure for the evaluation of oral hygiene among LT candidates.

Drug and alcohol positivity of traumatically injured patients related to COVID-19 stay-at-home orders.

Background: COVID-19 related stay-at-home (SAH) orders created many economic and social stressors, possibly increasing the risk of drug/alcohol abuse in the community and trauma population.Objectives: Describe changes in alcohol/drug use in traumatically injured patients after SAH orders in California and evaluate demographic or injury pattern changes in alcohol or drug-positive patients.Methods: A retrospective analysis of 11 trauma centers in Southern California (1/1/2020-6/30/2020) was performed. Blood alcohol concentration, urine toxicology results, demographics, and injury characteristics were collected. Patients were grouped based on injury date - before SAH (PRE-SAH), immediately after SAH (POST-SAH), and a historical comparison (3/19/2019-6/30/2019) (CONTROL) - and compared in separate analyses. Groups were compared using chi-square tests for categorical variables and Mann-Whitney U tests for continuous variables.Results: 20,448 trauma patients (13,634 male, 6,814 female) were identified across three time-periods. The POST-SAH group had higher rates of any drug (26.2% vs. 21.6% and 24.7%, OR = 1.26 and 1.08, p < .001 and p = .035), amphetamine (10.4% vs. 7.5% and 9.3%, OR = 1.43 and 1.14, p < .001 and p = .023), tetrahydrocannabinol (THC) (13.8% vs. 11.0% and 11.4%, OR = 1.30 and 1.25, p < .001 and p < .001), and 3,4-methylenedioxy methamphetamine (MDMA) (0.8% vs. 0.4% and 0.2%, OR = 2.02 and 4.97, p = .003 and p < .001) positivity compared to PRE-SAH and CONTROL groups. Alcohol concentration and positivity were similar between groups (p > .05).Conclusion: This Southern California multicenter study demonstrated increased amphetamine, MDMA, and THC positivity in trauma patients after SAH, but no difference in alcohol positivity or blood concentration. Drug prevention strategies should continue to be adapted within and outside of hospitals during a pandemic.

Single site versus conventional laparoscopic appendectomy: some pain for no gain?

INTRODUCTION: The optimal laparoscopic appendectomy approach is not clear, comparing single site laparoscopic appendectomy (SILA) to conventional 3-port appendectomy (CLA). We investigated outcomes in pediatric patients comparing SILA to CLA: length of operation, length of stay, time to resumption of regular diet, follow up, rehospitalization, and cost. METHODS: Data was collected from children 1 to 18 years with appendectomy at Loma Linda University from 2018 to 2020, operated by two surgeons. Analysis utilized two-sample T, chi-squared, and Fisher's exact tests. RESULTS: Of 173 patients, 77 underwent SILA and 96 had CLA. There was no gender, age, or race difference between groups. Mean WBC was 17.5 × 103/mL in SILA group, compared to 15.3 × 103/mL in CLA group (P = 0.004). Operative time was 47.0 SILA compared to 49.5 minutes CLA (P = 0.269). Of SILA cases, 55.8% were simple appendicitis, while 53.3% of the CLA cases were simple (P = 0.857). Regular diet was resumed after 1.7 days in the SILA group, 1.1 days in CLA (P = 0.018). Length of stay was 2.9 days for SILA, 2.4 days for CLA (P = 0.144). Seven children required hospital readmission, 5 SILA and 2 CLA (P = 0.244). Five of the children who returned had intra-abdominal abscesses, of whom 4 had SILA. There was no difference in cost. CONCLUSIONS: The operative techniques had similar outcomes and operative times. There was a trend toward more intra-abdominal abscesses in the SILA group. Further study and longer follow up is needed to determine if there is an advantage to one laparoscopic approach over another.

Cutaneous Manifestations of COVID-19.

Patients with coronavirus disease 2019 (COVID-19) present with multisystem signs and symptoms, including dermatologic manifestations. The recent literature has revealed that dermatologic manifestations of COVID-19 often are early onset and provide helpful cues to a timely diagnosis. We compiled the relevant emerging literature regarding the dermatologic manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) so that physicians can be aware of the various clinical cutaneous presentations in this time of high incidence of COVID-19.

The coronavirus disease 2019 (COVID-19) stay-at-home order's unequal effects on trauma volume by insurance status in Southern California.

BACKGROUND: The rapid spread of coronavirus disease 2019 in the United States led to a variety of mandates intended to decrease population movement and "flatten the curve." However, there is evidence some are not able to stay-at-home due to certain disadvantages, thus remaining exposed to both coronavirus disease 2019 and trauma. We therefore sought to identify any unequal effects of the California stay-at-home orders between races and insurance statuses in a multicenter study utilizing trauma volume data. METHODS: A posthoc multicenter retrospective analysis of trauma patients presenting to 11 centers in Southern California between the dates of January 1, 2020, and June 30, 2020, and January 1, 2019, and June 30, 2019, was performed. The number of trauma patients of each race/insurance status was tabulated per day. We then calculated the changes in trauma volume related to stay-at-home orders for each race/insurance status and compared the magnitude of these changes using statistical resampling. RESULTS: Compared to baseline, there was a 40.1% drop in total trauma volume, which occurred 20 days after stay-at-home orders. During stay-at-home orders, the average daily trauma volume of patients with Medicaid increased by 13.7 ± 5.3%, whereas the volume of those with Medicare, private insurance, and no insurance decreased. The average daily trauma volume decreased for White, Black, Asian, and Latino patients with the volume of Black and Latino patients dropping to a similar degree compared to White patients. CONCLUSION: This retrospective multicenter study demonstrated that patients with Medicaid had a paradoxical increase in trauma volume during stay-at-home orders, suggesting that the most impoverished groups remain disproportionately exposed to trauma during a pandemic, further exacerbating existing health disparities.