Changes in alcohol consumption and binge drinking during the COVID-19 pandemic among American Indians residing in California and Oklahoma.

Background: This study explored the increased quantity and frequency of alcohol use in the American Indian (AI) population during the COVID-19 pandemic.Objectives: The aims of this study were to explore possible associations between covariables and both binge drinking and alcohol consumption during COVID-19.Methods: This cross-sectional survey study analyzed data from a sample of AI individuals (63% female) residing in California (n = 411) and Oklahoma (n = 657) between October 2020-January 2021. Analysis included summary statistics and multivariable logistic regression, including a variety of socio-economic, COVID-19 concern, and tobacco and marijuana use variables.Results: One or more alcohol binge episodes were reported between October 2020-January 2021 in 19.3% of participants and elevated overall alcohol consumption was reported by 21.6% of participants. Higher odds of elevated alcohol consumption occurred in women and those following more social distancing measures. The odds of binge drinking or elevated alcohol consumption in those using both marijuana and tobacco (aOR/ adjusted odds ratio:18.9, 95% CI = 8.5, 42.2, and aOR:3.9, 95% CI = 1.7, 8.6, respectively) were higher compared to those using neither. Similarly, the odds of binge drinking or elevated alcohol consumption in those using tobacco only (aOR:4.7, 95% CI = 2.9, 7.7 and aOR: 2.0, 95% CI = 1.1, 3.5, respectively) were higher compared to those using neither.Conclusions: This study found high rates of alcohol use and bingeing during the COVID-19 pandemic. Offering collaborative, culturally sensitive, and affordable support services are important components of intervention and preparation for future stressful events on local, as well as global levels.

User Participatory Design of a Wearable Focal Vibration Device for Home-Based Stroke Rehabilitation.

Stroke often leads to the significant impairment of upper limb function and is associated with a decreased quality of life. Despite study results from several interventions for muscle activation and motor coordination, wide-scale adoption remains largely elusive due to under-doses and low user compliance and participation. Recent studies have shown that focal vibration has a greater potential to increase and coordinate muscle recruitment and build muscle strength and endurance. This form of treatment could widely benefit stroke survivors and therapists. Thus, this study aimed to design and develop a novel wearable focal vibration device for upper limb rehabilitation in stroke survivors. A user participatory design approach was used for the design and development. Five stroke survivors, three physical therapists, and two occupational therapists were recruited and participated. This pilot study may help to develop a novel sustainable wearable system providing vibration-based muscle activation for upper limb function rehabilitation. It may allow users to apply the prescribed vibratory stimuli in-home and/or in community settings. It may also allow therapists to monitor treatment usage and user performance and adjust the treatment doses based on progression.

Regulatory role of SphK1 in TLR7/9-dependent type I interferon response and autoimmunity.

Plasmacytoid dendritic cells (pDCs) express Toll like receptors (TLRs) that modulate the immune response by production of type I interferons. Here, we report that sphingosine kinase 1 (SphK1) which produces the bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P), plays a critical role in the pDC functions and interferon production. Although dispensable for the pDC development, SphK1 is essential for the pDC activation and production of type I IFN and pro-inflammatory cytokines stimulated by TLR7/9 ligands. SphK1 interacts with TLRs and specific inhibition or deletion of SphK1 in pDCs mitigates uptake of CpG oligonucleotide ligands by TLR9 ligand. In the pristane-induced murine lupus model, pharmacological inhibition of SphK1 or its genetic deletion markedly decreased the IFN signature, pDC activation, and glomerulonephritis. Moreover, increases in the SphK1 expression and S1P levels were observed in human lupus patients. Taken together, our results indicate a pivotal regulatory role for the SphK1/S1P axis in maintaining the balance between immunosurveillance and immunopathology and suggest that specific SphK1 inhibitors might be a new therapeutic avenue for the treatment of type I IFN-linked autoimmune disorders.

Examination of the role of sphingosine kinase 2 in a murine model of systemic lupus erythematosus.

Systemic lupus erythematosus is an autoimmune disease characterized by overproduction of type 1 IFN that causes multiple organ dysfunctions. Plasmacytoid dendritic cells (pDCs) that secrete large amounts of IFN have recently been implicated in the initiation of the disease in preclinical mouse models. Sphingosine-1-phosphate, a bioactive sphingolipid metabolite, is produced by 2 highly conserved isoenzymes, sphingosine kinase (SphK) 1 and SphK2, and regulates diverse processes important for immune responses and autoimmunity. However, not much is known about the role of SphK2 in autoimmune disorders. In this work, we examined the role of SphK2 in pDC development and activation and in the pristane-induced lupus model in mice that mimics the hallmarks of the human disease. Increases in pDC-specific markers were observed in peripheral blood of SphK2 knockout mice. In agreement, the absence of SphK2 increased the differentiation of FMS-like tyrosine kinase 3 ligand dendritic cells as well as expression of endosomal TLRs, TLR7 and TLR9, that modulate production of IFN. Surprisingly, however, SphK2 deficiency did not affect the initiation or progression of pristane-induced lupus. Moreover, although absence of SphK2 increased pDC frequency in pristane-induced lupus, there were no major changes in their activation status. Additionally, SphK2 expression was unaltered in lupus patients. Taken together, our results suggest that SphK2 may play a role in dendritic cell development. Yet, because its deletion had no effect on the clinical lupus parameters in this preclinical model, inhibitors of SphK2 might not be useful for treatment of this devastating disease.-Mohammed, S., Vineetha, N. S., James, S., Aparna, J. S., Lankadasari, M. B., Allegood, J. C., Li, Q.-Z., Spiegel, S., Harikumar, K. B. Examination of the role of sphingosine kinase 2 in a murine model of systemic lupus erythematosus.

Concurrent Validity of the School Outcomes Measure and the School Function Assessment in Elementary Students.

PURPOSE: Examine the concurrent validity of the School Outcomes Measure (SOM) and the School Function Assessment (SFA) in students kindergarten through sixth grade. METHODS: Twenty-four school-based therapists completed the SOM and the SFA for 42 students, representing Gross Motor Function Classification System (GMFCS) levels I to V. RESULTS: Correlation coefficients between SOM Self-Care, Mobility, and Assuming Student's Role median total scores and the 21 SFA Activity Performance scale median criterion scores were statistically significant. There were significant correlation coefficients between SOM Expressing Learning and Behavior and SFA median criterion scores. The SOM differentiated between GMFCS groups for all physical tasks but not cognitive/behavioral tasks, and the SFA for half of the physical tasks. CONCLUSIONS: Overall, student performance on the SOM was consistent with participation on the SFA, which lends support to the preliminary validity of the SOM. The GMFCS analysis suggests that the SOM differentiates between the GMFCS levels for physical tasks.

Experiences of women with cervical dysplasia and associated diagnoses using electronic cigarettes for smoking substitution.

INTRODUCTION: The aim of this qualitative study was to describe the motivation and experiences of women with cervical dysplasia and associated diagnoses who used electronic cigarettes (ECs) to reduce the number of cigarettes they smoked. METHODS: Qualitative interviews were conducted with 26 women aged 18-65 years with cervical dysplasia and associated diagnoses who smoked at least three cigarettes daily for the past year or more and who enrolled in an intervention designed to substitute regular cigarettes with ECs. At the 12-week follow-up, patients were contacted by telephone. Semi-structured interviews were recorded, then transcribed, coded and analysed for themes. RESULTS: When confronted with a new diagnosis associated with smoking, women in this study were eager to try ECs to help them reduce their intake of cigarettes. Women reported that physical cues similar to smoking, delivery of nicotine sufficient to assist with smoking reduction and the security of having the device available to use in instances where temptations to smoke may occur were all positive experiences in trying the device. Other women in the study reported negative experiences, such as a lack of sufficient nicotine to eliminate cravings, heaviness of the device and the need to keep it charged. Depression, nicotine addiction and habit were factors that made it difficult to decrease cigarette consumption. CONCLUSIONS: Findings suggest that ECs may help with smoking substitution in patients who must reduce smoking due to medical conditions or diagnoses.

Supercritical Angle Fluorescence Characterization Using Spatially Resolved Fourier Plane Spectroscopy.

Most fluorescent immunoassays require a wash step prior to read-out due to the otherwise overwhelming signal of the large number of unbound (bulk) fluorescent molecules that dominate over the signal from the molecules of interest, usually bound to a substrate. Supercritical angle fluorescence (SAF) sensing is one of the most promising alternatives to total internal reflection fluorescence for fluorescence imaging and sensing. However, detailed experimental investigation of the influence of collection angle on the SAF surface sensitivity, i.e., signal to background ratio (SBR), is still lacking. In this Letter, we present a novel technique that allows to discriminate the emission patterns of free and bound fluorophores simultaneously by collecting both angular and spectral information. The spectrum was probed at multiple positions in the back focal plane using a multimode fiber connected to a spectrometer and the difference in intensity between two fluorophores was used to calculate the SBR. Our study clearly reveals that increasing the angle of SAF collection enhances the surface sensitivity, albeit at the cost of decreased signal intensity. Furthermore, our findings are fully supported by full-field 3D simulations.

Electrically Driven Unidirectional Optical Nanoantennas.

Directional antennas revolutionized modern day telecommunication by enabling precise beaming of radio and microwave signals with minimal loss of energy. Similarly, directional optical nanoantennas are expected to pave the way toward on-chip wireless communication and information processing. Currently, on-chip integration of such antennas is hampered by their multielement design or the requirement of complicated excitation schemes. Here, we experimentally demonstrate electrical driving of in-plane tunneling nanoantennas to achieve broadband unidirectional emission of light. Far-field interference, as a result of the spectral overlap between the dipolar emission of the tunnel junction and the fundamental quadrupole-like resonance of the nanoantenna, gives rise to a directional radiation pattern. By tuning this overlap using the applied voltage, we record directivities as high as 5 dB. In addition to electrical tunability, we also demonstrate passive tunability of the directivity using the antenna geometry. These fully configurable electrically driven nanoantennas provide a simple way to direct optical energy on-chip using an extremely small device footprint.

Sex difference in brain functional connectivity of hippocampus in Alzheimer's disease.

Alzheimer's disease (AD), affecting nearly 6.5 million people, is the fifth leading cause of death in individuals 65 years or older in the USA. Prior research has shown that AD disproportionality affects females; females have a greater incidence rate, perform worse on a variety of neuropsychological tasks, and have greater total brain atrophy. Recent research has linked these sex differences to neuroimaging markers of brain pathology, such as hippocampal volumes. Specifically, research from our lab found that functional connectivity from the hippocampus to the precuneus cortex and brain stem was significantly stronger in males than in females with mild cognitive impairment. The aim of this study was to extend our understanding to individuals with AD and to determine if these potential sex-specific functional connectivity biomarkers extend through different disease stages. The resting state fMRI and T2 MRI of cognitively normal individuals (n = 32, female = 16) and individuals with AD (n = 32, female = 16) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed using the Functional Connectivity Toolbox (CONN). Our results demonstrate that males had a significantly stronger interhemispheric functional connectivity between the left and right hippocampus compared to females. These results improve our current understanding of the role of the hippocampus in sex differences in AD. Understanding the contribution of impaired functional connectivity sex differences may aid in the development of sex-specific precision medicine for improved AD treatment.

Corrigendum: High-definition transcranial direct current stimulation for upper extremity rehabilitation in moderate-to-severe ischemic stroke: a pilot study.

[This corrects the article DOI: 10.3389/fnhum.2023.1286238.].

Susceptibility to e-cigarette use and associated factors in high school youth, Oklahoma Youth Tobacco Survey, 2021-2022.

Introduction: Susceptibility predicts subsequent uptake of e-cigarettes (EC) by youth. This study identified factors associated with EC susceptibility among high school students who have never used a tobacco/nicotine product. Methods: The Oklahoma Youth Tobacco Survey was administered to a random sample of 36 Oklahoma High Schools during the 2021-2022 school year (n = 1,220 participating students). Associations between EC susceptibility and covariates were identified using stepwise logistic regression for weighted survey data. Results: More than one third of Oklahoma high school students who had never used tobacco or nicotine products (36.4%) were susceptible, and males had higher susceptibility than females (38.8 and 33.9%, respectively). In males, EC susceptibility was associated with race (Black, American Indian, and other were less susceptible), psychological distress (aOR = 2.4, 95% CI = 1.1, 4.8), disagreement that all tobacco products are dangerous (aOR = 3.1, 95% CI = 1.2, 7.9), and perception of little/no harm from secondhand vapor (aOR = 3.4, 95% CI = 2.1, 5.3). In females, identifying as gay, lesbian, or bisexual (aOR = 2.1, 95% CI = 1.1, 3.9), poor academic performance (aOR = 4.5, 95% CI = 1.6, 12.6), psychological distress (aOR = 2.6, 95% CI = 1.2, 5.5) and interacting with EC content on social media (aOR = 5.9, 95% CI = 1.9, 18.1) were associated with EC susceptibility. Conclusion: Males and females had different patterns of susceptibility to EC use. Understanding groups of adolescents most susceptible to using nicotine products can help target prevention efforts at home, in schools, and within communities.

Alteration in Resting-State Brain Activity in Stroke Survivors After Repetitive Finger Stimulation.

OBJECTIVE: This quasi-experimental study examined the effect of repetitive finger stimulation on brain activation in eight stroke and seven control subjects, measured by quantitative electroencephalogram. METHODS: We applied 5 mins of 2-Hz repetitive bilateral index finger transcutaneous electrical nerve stimulation and compared differences pre- and post-transcutaneous electrical nerve stimulation using quantitative electroencephalogram metrics delta/alpha ratio and delta-theta/alpha-beta ratio. RESULTS: Between-group differences before and after stimulation were significantly different in the delta/alpha ratio ( z = -2.88, P = 0.0040) and the delta-theta/alpha-beta ratio variables ( z = -3.90 with P < 0.0001). Significant decrease in the delta/alpha ratio and delta-theta/alpha-beta ratio variables after the transcutaneous electrical nerve stimulation was detected only in the stroke group (delta/alpha ratio diff = 3.87, P = 0.0211) (delta-theta/alpha-beta ratio diff = 1.19, P = 0.0074). CONCLUSIONS: The decrease in quantitative electroencephalogram metrics in the stroke group may indicate improved brain activity after transcutaneous electrical nerve stimulation. This finding may pave the way for a future novel therapy based on transcutaneous electrical nerve stimulation and quantitative electroencephalogram measures to improve brain recovery after stroke.

Sex differences in interacting genetic and functional connectivity biomarkers in Alzheimer's disease.

As of 2023, it is estimated that 6.7 million individuals in the United States live with Alzheimer's disease (AD). Prior research indicates that AD disproportionality affects females; females have a greater incidence rate, perform worse on a variety of neuropsychological tasks, and have greater total brain atrophy. Recent research shows that hippocampal functional connectivity differs by sex and may be related to the observed sex differences in AD, and apolipoprotein E (ApoE) ε4 carriers have reduced hippocampal functional connectivity. The purpose of this study was to determine if the ApoE genotype plays a role in the observed sex differences in hippocampal functional connectivity in Alzheimer's disease. The resting state fMRI and T2 MRI of individuals with AD (n = 30, female = 15) and cognitively normal individuals (n = 30, female = 15) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed using the functional connectivity toolbox (CONN). Our results demonstrated intrahippocampal functional connectivity differed between those without an ε4 allele and those with at least one ε4 allele in each group. Additionally, intrahippocampal functional connectivity differed only by sex when Alzheimer's participants had at least one ε4 allele. These results improve our current understanding of the role of the interacting relationship between sex, ApoE genotype, and hippocampal function in AD. Understanding these biomarkers may aid in the development of sex-specific interventions for improved AD treatment.

A Novel Combinatorial Regimen Using Sorafenib and Uttroside B, A US FDA-designated 'Orphan Drug', for the Treatment of Hepatocellular Carcinoma.

INTRODUCTION: Sorafenib (Sor) is the first-line treatment option in clinics for treating advanced unresectable hepatocellular carcinoma (HCC). However, acquired chemoresistance and adverse side effects associated with Sor monotherapy limit its clinical benefits. We have previously reported the exceptional anti-HCC potential of uttroside B (Utt-B), a furostanol saponin isolated in our lab from Solanum nigrum Linn. leaves. The current study has evaluated the supremacy of a combinatorial regimen of Sor and Utt-B over Sor monotherapy. METHODS: MTT assay was used for In vitro cytotoxicity studies. A clonogenic assay was conducted to assess the anti-proliferative effect of the combination. Annexin V/PI staining, confocal microscopy, FACS cell cycle analysis, and Western blotting experiments were performed to validate the pro-apoptotic potential of the combination in HepG2 and Huh7 cell lines. Pharmacological safety evaluation was performed in Swiss albino mice. RESULTS: Our results indicate that Utt-B augments Sor-induced cytotoxicity in HepG2 and Huh7 cells. The combination inhibits the proliferation of liver cancer cells by inducing apoptosis through activation of the caspases 7 and 3, leading to PARP cleavage. Furthermore, the combination does not induce any acute toxicity in vivo, even at a dose five times that of the effective therapeutic dose. CONCLUSION: Our results highlight the potential of Utt-B as an effective chemosensitizer, which can augment the efficacy of Sor against HCC and circumvent Sor-induced toxic side effects. Moreover, this is the first and only report to date on the chemosensitizing potential of Utt-B and the only report that demonstrates the therapeutic efficacy and pharmacological safety of a novel combinatorial regimen involving Utt-B and Sor for combating HCC.

Determining the effects of targeted high-definition transcranial direct current stimulation on reducing post-stroke upper limb motor impairments-a randomized cross-over study.

BACKGROUND: Stroke is one of the leading causes of death in the USA and is a major cause of serious disability for adults. This randomized crossover study examines the effect of targeted high-definition transcranial direct current transcranial brain stimulation (tDCS) on upper extremity motor recovery in patients in the post-acute phase of stroke recovery. METHODS: This randomized double-blinded cross-over study includes four intervention arms: anodal, cathodal, and bilateral brain stimulation, as well as a placebo stimulation. Participants receive each intervention in a randomized order, with a 2-week washout period between each intervention. The primary outcome measure is change in Motor Evoked Potential. Secondary outcome measures include the Fugl-Meyer Upper Extremity (FM-UE) score, a subset of FM-UE (A), related to the muscle synergies, and the Modified Ashworth Scale. DISCUSSION: We hypothesize that anodal stimulation to the ipsilesional primary motor cortex will increase the excitability of the damaged cortico-spinal tract, reducing the UE flexion synergy and enhancing UE motor function. We further hypothesize that targeted cathodal stimulation to the contralesional premotor cortex will decrease activation of the cortico-reticulospinal tract (CRST) and the expression of the upper extremity (UE) flexion synergy and spasticity. Finally, we hypothesize bilateral stimulation will achieve both results simultaneously. Results from this study could improve understanding of the mechanism behind motor impairment and recovery in stroke and perfect the targeting of tDCS as a potential stroke intervention. With the use of appropriate screening, we anticipate no ethical or safety concerns. We plan to disseminate these research results to journals related to stroke recovery, engineering, and medicine. TRIAL REGISTRATION: ClinicalTrials.gov NCT05479006 . Registered on 26 July 2022.

Determinants of healing and readiness for prosthetic fitting after transtibial amputation: Integrative literature review.

BACKGROUND: Healing after an amputation is a critical step in the recovery process. Delayed wound healing can lead to deconditioning and flexion contractures which reduce a patient's ability to use a prosthesis, ambulate independently, and return to community participation. The purpose of this integrative literature review was to determine the evidence-based physiological factors, comorbidities, postoperative management, and outcome measures associated with healing after transtibial amputation and address how these factors clinically guide readiness for prosthetic intervention. METHODS: Authors completed Google Scholar searches to identify the most effective search terms to locate salient publications. Authors also completed literature searches of Ovid MEDLINE and Epub Ahead of Print, In-Process, and Other Nonindexed Citations and Daily <1946 to August 6, 2020>; Embase Classic + Embase <1947 to August 6, 2020>; and CINAHL Complete <1946 to August 6, 2020> databases using the following search terms: "transtibial," "trans-tibial," "below knee," "BKA," "amputation," amputation stump," "amputee," "wound healing," and "heal/s/ed/ing." The authors decided to include all levels of evidence to capture the maximum number of articles related to the determinants of healing and readiness for prosthetic fitting after transtibial amputation. RESULTS: The searches identified 2067 potential articles for review, and after removing articles not relevant to the topic, authors completed full-text assessment on 20 articles. These included review and synthesis on three randomized controlled trials and 12 cohort studies. CONCLUSION: Preamputation assessment is most critical in patients who present with a longer list of comorbidities and suboptimal physiologic factors known to predict wound complications. Clinical judgment is most subjective when determining the degree of healing over time. Readiness for prosthetic treatment need not wait for complete healing of the residuum. Future research is needed to assess transcutaneous oxygen profusion along with other noninvasive measures of blood flow and perfusion as a more objective way to track progression of healing over time. This objective methodology would quantify healing, reduce subjectivity, and promote research to compare different enhanced recovery after surgery protocols for their impact on healing after amputation.

Predictors of Cessation in Men Using a Tobacco Quitline: A Follow-Up Study.

INTRODUCTION: Although the effectiveness of tobacco quitline services for people who smoke cigarettes is well established, less is known about other forms of tobacco. This study aimed to compare quit rates and factors contributing to tobacco abstinence in men reporting dual use (smokeless tobacco and one additional combustible tobacco product), smokeless tobacco use only, and cigarette use only. METHODS: Self-reported 30-day point-prevalence tobacco abstinence at the 7-month follow-up was calculated in males who registered with the Oklahoma Tobacco Helpline and completed a 7-month follow-up survey (N=3,721) (July 2015-November 2021). Logistic regression analysis completed in March 2023 identified variables associated with abstinence in each group. RESULTS: Abstinence was reported by 33% in the dual-use group, 46% in the smokeless-tobacco-use-only group, and 32% in the cigarette-use-only group. Eight or more weeks of nicotine replacement therapy provided by the Oklahoma Tobacco Helpline was associated with tobacco abstinence in men who reported dual use (AOR=2.7, 95% CI=1.2, 6.3) and exclusive smoking (AOR=1.6, 95% CI=1.1, 2.3). The use of all nicotine replacement therapy was associated with abstinence in men who used smokeless tobacco (AOR=2.1, 95% CI=1.4, 3.1) and who smoked (AOR=1.9, 95% CI=1.6, 2.3). The number of helpline calls was associated with abstinence in men who used smokeless tobacco (AOR=4.3, 95% CI=2.5, 7.3). CONCLUSIONS: Men in all three tobacco-use groups who fully utilized quitline services showed a greater likelihood of tobacco abstinence. These findings underscore the importance of quitline intervention as an evidence-based strategy for people who use multiple forms of tobacco.

High-definition transcranial direct current stimulation for upper extremity rehabilitation in moderate-to-severe ischemic stroke: a pilot study.

Introduction: Previous studies found that post-stroke motor impairments are associated with damage to the lesioned corticospinal tract (CST) and hyperexcitability of the contralesional cortico-reticulospinal tract (CRST). This proof-of-concept study aims to develop a non-invasive brain stimulation protocol that facilitates the lesioned CST and inhibits the contralesional CRST to improve upper extremity rehabilitation in individuals with moderate-to-severe motor impairments post-stroke. Methods: Fourteen individuals (minimum 3 months post ischemic stroke) consented. Physician decision of the participants baseline assessment qualified eight to continue in a randomized, double-blind cross-over pilot trial (ClinicalTrials.gov Identifier: NCT05174949) with: (1) anodal high-definition transcranial direct stimulation (HD-tDCS) over the ipsilesional primary motor cortex (M1), (2) cathodal HD-tDCS over contralesional dorsal premotor cortex (PMd), (3) sham stimulation, with a two-week washout period in-between. Subject-specific MR images and computer simulation were used to guide HD-tDCS and verified by Transcranial Magnetic Stimulation (TMS) induced Motor Evoked Potential (MEP). The motor behavior outcome was evaluated by an Fugl-Meyer Upper Extremity score (primary outcome measure) and the excitability of the ipslesoinal CST and contralesional CRST was determined by the change of MEP latencies and amplitude (secondary outcome measures). Results: The baseline ipsilesional M1 MEP latency and amplitude were correlated with FM-UE. FM-UE scores were improved post HD-tDCS, in comparison to sham stimulation. Both anodal and cathodal HD-tDCS reduced the latency of the ipsilesional M1 MEP. The contralesional PMd MEP disappeared/delayed after HD-tDCS. Discussion: These results suggest that HD-tDCS could improve the function of the lesioned corticospinal tract and reduce the excitability of the contralesional cortico-reticulospinal tract, thus, improving motor function of the upper extremity in more severely impaired individuals.

Avoidance of medical care among American Indians with a history of cancer during the coronavirus pandemic.

Objectives: Assess the percentage of cancer-related appointment delays, cancelations, and the unavailability of medications experienced by American Indian participants during the COVID-19 pandemic. Methods: This cross-sectional survey study was completed between October 2020 and July 2021 by 360 individuals with cancer who lived in California and Oklahoma. Binary and multivariate logistic regression analysis was completed in SAS 9.4. Results: During the initial Covid-19 pandemic, almost one-third (30%) of respondents delayed cancer-related appointments, 42% canceled cancer-related appointments, and one-quarter (24%) were unable to access prescription medications or over-the-counter medications (27%) due to COVID-19. People who underwent testing for COVID-19 were five times more likely to delay a medical appointment [adjusted odds ratio (aOR) = 5.3, 95% CI:2.4, 11.7] and people who followed three or more social distancing measures were more than six times more likely to cancel medical appointments (aOR:6.3, 95% CI:2.9, 13.9). Conclusion: This study identifies delays, cancelations, and medication inaccessibility people identifying as American Indian faced during the coronavirus pandemic. Disparities in healthcare delivery could contribute to increased morbidity and mortality rates of cancer.

Targeting acid ceramidase enhances antitumor immune response in colorectal cancer.

INTRODUCTION: Acid ceramidase (hereafter referred as ASAH1) is an enzyme in sphingolipid metabolism that converts pro-survival ceramide into sphingosine. ASAH1 has been shown to be overexpressed in certain cancers. However, the role of ASAH1 in colorectal cancer still remain elusive. OBJECTIVE: The present study is aimed to understand how ASAH1 regulates colorectal cancer (CRC) progression and resistance to checkpoint inhibitor therapy. METHODS: Both pharmacological and genetic silencing of ASAH1 was used in the study. In vitro experiments were done on human and mouse CRC cell lines. The in vivo studies were conducted in NOD-SCID and BALB/c mice models. The combination of ASAH1 inhibitor and checkpoint inhibitor was tested using a syngeneic tumor model of CRC. Transcriptomic and metabolomic analyses were done to understand the effect of ASAH1 silencing. RESULTS: ASAH1 is overexpressed in human CRC cases, and silencing the expression resulted in the induction of immunological cell death (ICD) and mitochondrial stress. The ASAH1 inhibitor (LCL-521), either as monotherapy or in combination with an anti-PD-1 antibody, resulted in reduction of tumors and, through induction of type I and II interferon response, activation of M1 macrophages and T cells, leading to enhanced infiltration of cytotoxic T cells. Our findings supported that the combination of LCL-521 and ICIs, which enhances the antitumor responses, and ASAH1 can be a druggable target in CRC.