Effects of the Brief Simha Kriya Breathing Practice for Health Care Workers During the COVID-19 Pandemic.

Introduction: During the COVID-19 pandemic, health care workers (HCWs) experienced increased anxiety, depression, loneliness, and other mental health issues. HCWs need additional resources to cope with the mental health impact of their work. Yoga techniques could be helpful strategies to manage different stressors during times of uncertainty. Methods: This prospective, single-arm, trial examined the effects of a brief pranayama yoga practice on the wellbeing of HCWs during the height of COVID-19. HCWs were recruited through announcements and institutional websites at a large major cancer center in the southern United States. A short, prerecorded, 5-min breathwork video intervention called "Simha Kriya" was provided to participants, and they were encouraged to practice one to two times daily for 4 weeks. Participants completed self-report instruments at baseline and weeks 1 and 4, including: (1) Perceived Stress Scale (PSS); (2) Brief Resilient Coping Scale (BRCS); and (3) a questionnaire assessing the experience of COVID-19 among HCWs that had five subscales. HCWs also conducted a measure of breath holding time. Paired sample t-tests and mixed-effects analysis of variance models examined changes over time. Results: One hundred participants consented to the study, with 88 female, 60 white, 39 worked remotely, and 27 were clinical staff. Sixty-nine participants provided data at week 1 and 56 at week 4. Participants' adherence to the breathing exercises between weeks 1 and 4 was similar, with a mean of six times per week. At week 4, there were significant decreases in the COVID-19 Distress score (p < 0.0001) and COVID-19 Disruption (p = 0.013), yet no changes in the PSS. There were also significant increases in COVID-19 Stress Management (p = 0.0001) and BRCS scores (p = 0.012), but no changes in Perceived Benefits of COVID-19 and no changes in breath holding time. Discussion: Brief yoga-based breathing practices helped reduce pandemic-specific stress, improved resilience, and stress management skills in HCWs. Trial Registration Number: NCT04482647.

Treatment of localized hepatocellular carcinoma: resection vs. ablation vs. radiation.

Hepatocellular carcinoma (HCC) is a common malignancy with many patients presenting with local disease. As of date, the use of radiation is not included in the commonly utilized Barcelona Clinic Liver Cancer (BCLC) classification but is in the National Comprehensive Cancer Network guidelines. Radiation can volumetrically cover the entire tumor and with novel technologic advances can be administered non-invasively with excellent clinical outcomes with few adverse events. The gold standard for localized early HCC (such as BCLC-A) is resection or transplantation. In patients who are not candidates for surgical treatment, locoregional therapy should be considered as an optimal therapy for these patients. Tumor ablation techniques such as microwave ablation (MWA) and radiofrequency ablation (RFA) are excellent tools to control local disease or bridge to transplantation. Should these not be possible though then ablation with external beam radiation is also capable of yielding comparable local control and serve as a bridge to transplant without worse rates of adverse events. For tumors that meet Milan criteria for transplantation, in comparison to transarterial chemoembolization (TACE), there is considerable randomized evidence demonstrating better local control, less adverse events, better progression-free survival (PFS), and less costly. It can be utilized as a bridge in Barcelona liver class B. For larger localized tumors though (extrahepatic disease or vascular invasion like BCLC-C), stereotactic body radiation therapy (SBRT) is shown via a randomized clinical trial to have a survival benefit, local control benefit, and no worse adverse events compared to systemic therapy. In this setting, it should be considered the local consolidation standard of care.

Network Localization of Unconscious Visual Perception in Blindsight.

OBJECTIVE: Blindsight is a disorder where brain injury causes loss of conscious but not unconscious visual perception. Prior studies have produced conflicting results regarding the neuroanatomical pathways involved in this unconscious perception. METHODS: We performed a systematic literature search to identify lesion locations causing visual field loss in patients with blindsight (n = 34) and patients without blindsight (n = 35). Resting state functional connectivity between each lesion location and all other brain voxels was computed using a large connectome database (n = 1,000). Connections significantly associated with blindsight (vs no blindsight) were identified. RESULTS: Functional connectivity between lesion locations and the ipsilesional medial pulvinar was significantly associated with blindsight (family wise error p = 0.029). No significant connectivity differences were found to other brain regions previously implicated in blindsight. This finding was independent of methods (eg, flipping lesions to the left or right) and stimulus type (moving vs static). INTERPRETATION: Connectivity to the ipsilesional medial pulvinar best differentiates lesion locations associated with blindsight versus those without blindsight. Our results align with recent data from animal models and provide insight into the neuroanatomical substrate of unconscious visual abilities in patients. ANN NEUROL 2022;91:217-224.

Phase II Trial of Ipilimumab with Stereotactic Radiation Therapy for Metastatic Disease: Outcomes, Toxicities, and Low-Dose Radiation-Related Abscopal Responses.

Ipilimumab is effective for patients with melanoma, but not for those with less immunogenic tumors. We report a phase II trial of ipilimumab with concurrent or sequential stereotactic ablative radiotherapy to metastatic lesions in the liver or lung (NCT02239900). Ipilimumab (every 3 weeks for 4 doses) was given with radiotherapy begun during the first dose (concurrent) or 1 week after the second dose (sequential) and delivered as 50 Gy in 4 fractions or 60 Gy in 10 fractions to metastatic liver or lung lesions. In total, 106 patients received ≥1 cycle of ipilimumab with radiation. Median follow-up was 10.5 months. Median progression-free survival time was 2.9 months (95% confidence interval, 2.45-3.40), and median overall survival time was not reached. Rates of clinical benefit of nonirradiated tumor volume were 26% overall, 28% for sequential versus 20% for concurrent therapy (P = 0.250), and 31% for lung versus 14% for liver metastases (P = 0.061). The sequential lung group had the highest rate of clinical benefit at 42%. There were no differences in treatment-related adverse events between groups. Exploratory analysis of nontargeted lesions revealed that lesions receiving low-dose radiation were more likely to respond than those that received no radiation (31% vs. 5%, P = 0.0091). This phase II trial of ipilimumab with stereotactic radiotherapy describes satisfactory outcomes and low toxicities, lending support to further investigation of combined-modality therapy for metastatic cancers.

Children with appendicitis on the US-Mexico border have socioeconomic challenges and are best served by a freestanding children's hospital.

INTRODUCTION: The US-Mexico border is medically underserved. Recent political changes may render this population even more vulnerable. We hypothesized that children on the border present with high rates of perforated appendicitis due to socioeconomic barriers. METHODS: A prospective survey was administered to children presenting with appendicitis in El Paso, Texas. Primary outcomes were rate of perforation and reason for diagnostic delay. We evaluated the association between demographics, potential barriers to care, risk of perforation and risk of misdiagnosis using logistic regression. p < 0.05 was considered significant. RESULTS: 98 patients participated from October 2016 to February 2017. 96 patients (98%) were Hispanic and 81 (82%) had Medicaid or were uninsured. 11 patients (11%) resided in Mexico or Guatemala. Patients were less likely to receive a CT and more likely to receive an ultrasound if they presented to a freestanding children's hospital (p = 0.01). 37 patients (38%) presented with perforation, of which 19 (52%) were the result of practitioner misdiagnosis. Patients who presented to a freestanding children's hospital were less likely to be misdiagnosed than patients presenting to other facilities (p = 0.05). Children who underwent surgery in a freestanding children's hospital had the shortest length of stay after adjusting for perforation status and potential confounders (p < 0.01). CONCLUSION: Children with low socioeconomic status did not have difficulty accessing care on the USA-Mexico border, but they were commonly misdiagnosed. Children were less likely to receive a CT, more likely to be correctly diagnosed and length of stay was shorter when patients presented to a freestanding children's hospital.

Accuracy and Precision of an Optoacoustic Prototype in Determining Endotracheal Tube Position in Children.

BACKGROUND: Confirmation of endotracheal tube (ETT) tip position and timely identification and correction of malposition is an essential component of care for endotracheally intubated and mechanically ventilated children. We evaluated the ability of a prototype optoacoustic medical device to determine ETT tip position. We hypothesized that the precision of optoacoustic assessment of ETT tip position would be comparable to chest radiography. METHODS: We recruited children aged newborn to 16 y who were admitted to the pediatric ICU requiring tracheal intubation and undergoing a chest radiograph for clinical purposes. After positioning each child on a chest radiograph plate, a sterile optical fiber, temporarily inserted through the ETT, emitted laser pulses perpendicular to the fiber and to the ETT, generating acoustic (ultrasound) waves in overlying tissue when the tip of the fiber passed beneath an acoustic sensor in the sternal notch. The distance from the ETT tip to the peak acoustic signal was used to calculate the distance from the ETT tip to the carina, which was compared with the same distance calculated by the radiologist reading the chest radiograph. Pearson's correlation coefficient, paired t tests, a Bland-Altman plot were used to compare the measures (P < .05 was considered statistically significant). RESULTS: Twenty-six subjects were enrolled: 15 (57.7%) were male, median (interquartile range) age, weight, and height were 9 months (4-24), 9.6 kg (5.7-13.0), and 75 cm (62-90), respectively. All ETTs were cuffed (internal diameter range 3.0-5.0 mm). The relationship between optoacoustic and chest radiograph measurements was strong (r = 0.91, P < .001). Bias was 0.1 cm with narrow limits of agreement between measures (0.58 cm and 0.76 cm). CONCLUSIONS: The optoacoustic prototype accurately determined ETT tip position and was comparable in precision to chest radiograph.

Penetrating trauma in children on the United States-Mexico border: Hispanic ethnicity is not a risk factor.

INTRODUCTION: The United States-Mexico border is perceived as dangerous by the media and current political leaders. Hispanic ethnicity, low socioeconomic status, male gender and adolescent age have previously been identified as risk factors for penetrating trauma (PT). METHODS: A retrospective review of PT was performed in a border region. Children 0-17 years old, admitted to the region's only level I trauma center between 2001 and 2016 were included. Standardized morbidity ratio was used to compare observed to expected morbidity. RESULTS: There were 417 PT admissions. 197 (47%) were non-accidental, 34 (8%) suicide attempts and 186 (45%) accidental. There were 12 homicides, 7 suicides and no accidental deaths. The region contains over 280,000 children, thus yielding a homicide rate of 0.26 per 100,000. The U.S. pediatric homicide rate was 2.6-4.0 over this period. Adolescents 13-17 years old accounted for 237 (57%) admissions, 152 (78%) of non-accidental admissions and 12 (63%) deaths. Most admissions (N = 321, 77%) and 15 of the deaths (79%) were males. Non-accidental injuries were more frequent in ZIP codes associated with low incomes. Hispanic patients accounted for 173 (88%) of non-accidental trauma. However, 40 (20%) non-accidental injuries occurred in Mexico and 157 (80%) injuries occurred in an 82% Hispanic region. Therefore, the standardized morbidity ratio for Hispanic ethnicity was 1.048 (CL 0.8-1.2, P = 0.6). CONCLUSION: On the United States-Mexico border, the pediatric homicide rate was less than 1/10 the national average. Male adolescents are at risk for non-accidental PT. In a Hispanic majority population, Hispanic ethnicity was not a risk factor for PT. It is possible that economic disparity, rather than race/ethnicity, is a risk factor for PT.

Radiation therapy and immunotherapy: what is the optimal timing or sequencing?

Radiotherapy is a component of the standard of care for many patients with locally advanced nonmetastatic tumors and increasingly those with oligometastatic tumors. Despite encouraging advances in local control and progression-free and overall survival outcomes, continued manifestation of tumor progression or recurrence leaves room for improvement in therapeutic efficacy. Novel combinations of radiation with immunotherapy have shown promise in improving outcomes and reducing recurrences by overcoming tumor immune tolerance and evasion mechanisms via boosting the immune system's ability to recognize and eradicate tumor cells. In this review, we discuss preclinical and early clinical evidence that radiotherapy and immunotherapy can improve treatment outcomes for locally advanced and metastatic tumors, elucidate underlying molecular mechanisms and address strategies to optimize timing and sequencing of combination therapy for maximal synergy.

Radiation and Anti-Cancer Vaccines: A Winning Combination.

The emerging combination of radiation therapy with vaccines is a promising new treatment plan in the fight against cancer. While many cancer vaccines such as MUC1, p53 CpG oligodeoxynucleotide, and SOX2 may be great candidates for antitumor vaccination, there still remain many investigations to be done into possible vaccine combinations. One fruitful partnership that has emerged are anti-tumor vaccines in combination with radiation. Radiation therapy was previously thought to be only a tool for directly or indirectly damaging DNA and therefore causing cancer cell death. Now, with much preclinical and clinical data, radiation has taken on the role of an in situ vaccine. With both cancer vaccines and radiation at our disposal, more and more studies are looking to combining vaccine types such as toll-like receptors, viral components, dendritic-cell-based, and subunit vaccines with radiation. While the outcomes of these combinatory efforts are promising, there is still much work to be covered. This review sheds light on the current state of affairs in cancer vaccines and how radiation will bring its story into the future.

Uncovering the immune tumor microenvironment in non-small cell lung cancer to understand response rates to checkpoint blockade and radiation.

The study of immunology has led to breakthroughs in treating non-small cell lung cancer (NSCLC). The recent approval of an anti-PD1 checkpoint drug for NSCLC has generated much interest in novel combination therapies that might provide further benefit for patients. However, a better understanding of which combinations may (or may not) work in NSCLC requires understanding the lung immune microenvironment under homeostatic conditions and the changes in that microenvironment in the setting of cancer progression and with radiotherapy. This review provides background information on immune cells found in the lung and the prognostic significance of these cell types in lung cancer. It also addresses current clinical directions for the combination of checkpoint inhibitors with radiation for NSCLC.

Mouse Liver Sinusoidal Endothelium Eliminates HIV-Like Particles from Blood at a Rate of 100 Million per Minute by a Second-Order Kinetic Process.

We crafted human immunodeficiency virus (HIV)-like particles of diameter about 140 nm, which expressed two major HIV-1 proteins, namely, env and gag gene products, and used this reagent to simulate the rate of decay of HIV from the blood stream of BALB/c male mice. We found that most (~90%) of the particles were eliminated (cleared) from the blood by the liver sinusoidal endothelial cells (LSECs), the remainder from Kupffer cells; suggesting that LSECs are the major liver scavengers for HIV clearance from blood. Decay was rapid with kinetics suggesting second order with respect to particles, which infers dimerization of a putative receptor on LSEC. The number of HIV-like particles required for saturating the clearance mechanism was approximated. The capacity for elimination of blood-borne HIV-like particles by the sinusoid was 112 million particles per minute. Assuming that the sinusoid endothelial cells were about the size of glass-adherent macrophages, then elimination capacity was more than 540 particles per hour per endothelial cell.

Blood-Borne Lipopolysaccharide Is Rapidly Eliminated by Liver Sinusoidal Endothelial Cells via High-Density Lipoprotein.

During Gram-negative bacterial infections, excessive LPS induces inflammation and sepsis via action on immune cells. However, the bulk of LPS can be cleared from circulation by the liver. Liver clearance is thought to be a slow process mediated exclusively by phagocytic resident macrophages, Kupffer cells (KC). However, we discovered that LPS disappears rapidly from the circulation, with a half-life of 2-4 min in mice, and liver eliminates about three quarters of LPS from blood circulation. Using microscopic techniques, we found that ∼75% of fluor-tagged LPS in liver became associated with liver sinusoidal endothelial cells (LSEC) and only ∼25% with KC. Notably, the ratio of LSEC-KC-associated LPS remained unchanged 45 min after infusion, indicating that LSEC independently processes the LPS. Most interestingly, results of kinetic analysis of LPS bioactivity, using modified limulus amebocyte lysate assay, suggest that recombinant factor C, an LPS binding protein, competitively inhibits high-density lipoprotein (HDL)-mediated LPS association with LSEC early in the process. Supporting the previous notion, 3 min postinfusion, 75% of infused fluorescently tagged LPS-HDL complex associates with LSEC, suggesting that HDL facilitates LPS clearance. These results lead us to propose a new paradigm of LSEC and HDL in clearing LPS with a potential to avoid inflammation during sepsis.

Scavenger receptor B1, the HDL receptor, is expressed abundantly in liver sinusoidal endothelial cells.

Cholesterol from peripheral tissue, carried by HDL, is metabolized in the liver after uptake by the HDL receptor, SR-B1. Hepatocytes have long been considered the only liver cells expressing SR-B1; however, in this study we describe two disparate immunofluorescence (IF) experiments that suggest otherwise. Using high-resolution confocal microscopy employing ultrathin (120 nm) sections of mouse liver, improving z-axis resolution, we identified the liver sinusoidal endothelial cells (LSEC), marked by FcγRIIb, as the cell within the liver expressing abundant SR-B1. In contrast, the hepatocyte, identified with ß-catenin, expressed considerably weaker levels, although optical resolution of SR-B1 was inadequate. Thus, we moved to a different IF strategy, first separating dissociated liver cells by gradient centrifugation into two portions, hepatocytes (parenchymal cells) and LSEC (non-parenchymal cells). Characterizing both portions for the cellular expression of SR-B1 by flow cytometry, we found that LSEC expressed considerable amounts of SR-B1 while in hepatocytes SR-B1 expression was barely perceptible. Assessing mRNA of SR-B1 by real time PCR we found messenger expression in LSEC to be about 5 times higher than in hepatocytes.

Providing neurologic care in criminal systems and state mental hospitals.

As health care laws and payment structures change in the near future, neurologists may pursue other practice settings in which to provide care as a way to diversify their practice. Here we describe the challenges and opportunities involved with working in correctional and state mental hospital systems compared to a typical private practice: logistical challenges, patient and provider safety, patient characteristics, and cultural differences. Neurologists may take these factors into consideration when choosing whether to add this health care setting to their current practice.

Surmounting an impasse of FcRn structure.

FcRn, resembling a major histocompatibility complex class I molecule with a closed peptide cleft, is an intracellular molecule that binds endocytosed albumin and IgG by a pH-dependent mechanism, diverting them from degradative fates and moving them out of the cell. The turnover of both of these important plasma proteins is thus regulated, as discussed by Schmidt and colleagues in this issue of Structure.

Abundant intracellular IgG in enterocytes and endoderm lacking FcRn.

FcRn, a non-classical MHCI molecule, transports IgG from mother to young and regulates the rate of IgG degradation throughout life. Brambell proposed a mechanism that unified these two functions, saying that IgG was pinocytosed nonspecifically by the cell into an FcRn-expressing endosome, where, at low pH, it bound to FcRn and was exocytosed. This theory was immediately challenged by claims that FcRn specificity for ligand could be conferred at the cell surface in neonatal jejunum. Assessing Brambell's hypothesis we found abundant nonspecifically endocytosed IgG present in the cytoplasm of FcRn(-/-) enterocytes. Further, IgG was present in the intercellular clefts and the cores of FcRn(+/+) but not FcRn(-/-) jejunum. FcRn specificity for ligand could be determined within the cell.