Promotion of an Antitumor Immune Program by a Tumor-specific, Complement-activating Antibody.

Tumor-targeting Abs can be used to initiate an antitumor immune program, which appears essential to achieve a long-term durable clinical response to cancer. We previously identified an anti-complement factor H (CFH) autoantibody associated with patients with early-stage non-small cell lung cancer. We cloned from their peripheral B cells an mAb, GT103, that specifically recognizes CFH on tumor cells. Although the underlying mechanisms are not well defined, GT103 targets a conformationally distinct CFH epitope that is created when CFH is associated with tumor cells, kills tumor cells in vitro, and has potent antitumor activity in vivo. In the effort to better understand how an Ab targeting a tumor epitope can promote an effective antitumor immune response, we used the syngeneic CMT167 lung tumor C57BL/6 mouse model, and we found that murinized GT103 (mGT103) activates complement and enhances antitumor immunity through multiple pathways. It creates a favorable tumor microenvironment by decreasing immunosuppressive regulatory T cells and myeloid-derived suppressor cells, enhances Ag-specific effector T cells, and has an additive antitumor effect with anti-PD-L1 mAb. Furthermore, the immune landscape of tumors from early-stage patients expressing the anti-CFH autoantibody is associated with an immunologically active tumor microenvironment. More broadly, our results using an mAb cloned from autoantibody-expressing B cells provides novel, to our knowledge, mechanistic insights into how a tumor-specific, complement-activating Ab can generate an immune program to kill tumor cells and inhibit tumor growth.

First- vs second-line CDK 4/6 inhibitor use for patients with hormone receptor positive, human epidermal growth-factor receptor-2 negative, metastatic breast cancer in the real world setting.

PURPOSE: To compare CDK4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) in the first- versus second-line setting for treatment of hormone receptor positive (HR+), HER2 negative, metastatic breast cancer (MBC) using real-world evidence. METHODS: Patients with HR+, HER2 negative MBC, diagnosed between 2/3/2015 and 11/2/2021 and having ≥ 3 months follow-up were identified from the nationwide electronic health record-derived Flatiron Health de-identified database. Treatment cohorts included: (1) first-line ET with a CDK 4/6i (1st-line CDK4/6i) versus (2) first-line ET alone followed by second-line ET with a CDK4/6i (2nd-line CDK4/6i). Differences in baseline characteristics were tested using chi-square tests and two-sample t-tests. Time to third-line therapy, time to start of chemotherapy, and overall survival were compared using Kaplan-Maier method. RESULTS: The analysis included 2771 patients (2170 1st-line CDK4/6i and 601 2nd-line CDK4/6i). Patients receiving 1st-line CDK4/6i were younger (75% vs 68% < 75 years old, p = 0.0001), less likely uninsured or not having insurance status documented (10% vs. 13%, p = 0.04), of better performance status (50% vs 43% with ECOG 0, p = 0.03), and more likely to have de novo MBC (36% vs. 24%, p < 0.001). Time to third-line therapy (49 vs 22 months, p < 0.001) and time to chemotherapy (68 vs 41 months, p < 0.001) were longer in those receiving first-line CDK4/6i. Overall survival (54 vs 49 months, p = 0.33) was similar between groups. CONCLUSION: Use of CDK4/6i with first-, vs second-, line ET was associated with longer time to receipt of 3rd-line therapy and longer time to receipt of chemotherapy.

Impact of HER2-low status for patients with early-stage breast cancer and non-pCR after neoadjuvant chemotherapy: a National Cancer Database Analysis.

PURPOSE: To investigate potential differences in pathological complete response (pCR) rates and overall survival (OS) between HER2-low and HER2-zero patients with early-stage hormone receptor (HR)-positive and triple-negative breast cancer (TNBC), in the neoadjuvant chemotherapy setting. METHODS: We identified early-stage invasive HER2-negative BC patients who received neoadjuvant chemotherapy diagnosed between 2010 and 2018 in the National Cancer Database. HER2-low was defined by immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization, and HER2-zero by IHC0. All the methods were applied separately in the HR-positive and TNBC cohorts. Logistic regression was used to estimate the association of HER2 status with pCR (i.e. ypT0/Tis and ypN0). Kaplan-Meier method and Cox proportional hazards model were applied to estimate the association of HER2 status with OS. Inverse probability weighting and/or multivariable regression were applied to all analyses. RESULTS: For HR-positive patients, 70.9% (n = 17,934) were HER2-low, whereas 51.1% (n = 10,238) of TNBC patients were HER2-low. For both HR-positive and TNBC cohorts, HER2-low status was significantly associated with lower pCR rates [HR-positive: 5.0% vs. 6.7%; weighted odds ratio (OR) = 0.81 (95% CI: 0.72-0.91), p < 0.001; TNBC: 21.6% vs. 24.4%; weighted OR = 0.91 (95% CI: 0.85-0.98), p = 0.007] and improved OS [HR-positive: weighted hazard ratio = 0.85 (95% CI: 0.79-0.91), p < 0.001; TNBC: weighted hazard ratio = 0.91 (95% CI: 0.86-0.96), p < 0.001]. HER2-low status was associated with favorable OS among patients not achieving pCR [HR-positive: adjusted hazard ratio = 0.83 (95% CI: 0.77-0.89), p < 0.001; TNBC: adjusted hazard ratio = 0.88 (95% CI 0.83-0.94), p < 0.001], while no significant difference in OS was observed in patients who achieved pCR [HR-positive: adjusted hazard ratio = 1.00 (95% CI: 0.61-1.63), p > 0.99; TNBC: adjusted hazard ratio = 1.11 (95% CI: 0.85-1.45), p = 0.44]. CONCLUSION: In both early-stage HR-positive and TNBC patients, HER2-low status was associated with lower pCR rates. HER2-zero status might be considered an adverse prognostic factor for OS in patients not achieving pCR.

Prevalence of Cognitive and Manual Dexterity Disorders Among Men Following Artificial Urinary Sphincter Placement.

PURPOSE: Cognitive ability and manual dexterity sufficient to operate an artificial urinary sphincter (AUS) are critical for device function and safety. We aimed to define the incidence of cognitive and/or dexterity disorders among men after AUS. We secondarily aimed to assess for association between these disorders and postimplant complications. MATERIALS AND METHODS: This is a retrospective cohort study using the SEER (Surveillance, Epidemiology, and End Results)-Medicare linked database (2000-2018). We included men ≥ 66 years diagnosed with prostate cancer between 2001 to 2015 who subsequently underwent AUS placement. We excluded patients with < 1-year continuous fee-for-service Medicare enrollment or cognitive and/or manual dexterity disorder diagnoses prior to AUS implant. Subsequent cognitive/dexterity disorders and implant-related complications were queried using appropriate ICD (International Classification of Diseases)-9/10 and/or CPT (Current Procedural Terminology) codes. Associations between cognitive/dexterity disorders and postimplant complications were assessed using extended Cox proportional hazards modeling. Secondary analysis focused on serious complications (device revision/removal, Fournier's gangrene, urethral erosion). RESULTS: We identified 1560 men who underwent AUS who met inclusion criteria. Median age was 73.0 (IQR 70-77) years. Cumulative incidence function analysis estimated 44% and 17% incidence of cognitive and manual dexterity disorder, respectively, at 15 years post-AUS. Presence of cognitive with/without manual dexterity disorder was associated with increased hazard of any, but not serious, complication during follow-up. CONCLUSIONS: A significant proportion of patients develop cognitive and/or manual dexterity disorders following AUS. These data support the need for close longitudinal monitoring after implant.

A Potential Role of Interleukin 10 in COVID-19 Pathogenesis.

A unique feature of the cytokine storm in coronavirus disease 2019 (COVID-19) is the dramatic elevation of interleukin 10 (IL-10). This was thought to be a negative feedback mechanism to suppress inflammation. However, several lines of clinical evidence suggest that dramatic early proinflammatory IL-10 elevation may play a pathological role in COVID-19 severity.

A retrospective cost-effectiveness analysis of different cognitive-behavioral therapy for insomnia intervention delivery approaches in adult cancer survivors.

BACKGROUND: Cognitive-behavioral therapy for insomnia (CBT-I) is considered the gold standard treatment for insomnia. Prior trials have delivered CBT-I across a range of treatment sessions. Understanding the economics of varying treatment approaches is essential for future implementation considerations. METHODS: We conducted a retrospective cost-effectiveness analysis from the provider's perspective, comparing the implementation of a three-session CBT-I program for cancer survivors (CBT-I-CS) versus a stepped care treatment approach consisting of an initial single sleep education session followed by CBT-I-CS if elevated insomnia symptoms persisted. The effectiveness measure used was the percentage of participants whose insomnia had remitted by the end of each program. RESULTS: Stepped care delivery was more effective than CBT-I-CS alone, resulting in 35.4% more remitted patients by the end of the overall program. For a $480 willingness to pay threshold per percentage of remitted patients, stepped care CBT-I-CS reached a 98% probability of being cost-effective, while CBT-I-CS alone had only a 2% probability. Larger group sessions in the first step of a stepped care delivery model resulted in more favorable cost-effectiveness. CONCLUSIONS: A stepped care delivery model may be a more cost-effective approach if it can be implemented efficiently. These findings inform policies aimed at improving cancer survivors' access to much-needed insomnia treatment in settings where financial resources for CBT-I may be limited, and be an important barrier to treatment dissemination. CLINICAL TRIAL REGISTRATION: These analyses were not registered.

Caregivers' Internet-Delivered Insomnia Intervention Engagement and Benefit: SHUTi-CARE Trial Primary Quantitative Analysis.

BACKGROUND: Delivering insomnia treatment by the Internet holds promise for increasing care access to family caregivers, but their ability to adhere to and benefit from such fully-automated programs has not been rigorously tested. PURPOSE: This fully-powered, single-group trial tested whether characteristics of the caregiving context influence high-intensity caregivers' engagement with and benefit from an empirically validated Internet intervention for insomnia. METHODS: At baseline, caregivers providing unpaid time- and responsibility-intensive care who reported insomnia (N = 100; age M = 52.82 [SD = 13.10], 75% non-Hispanic white, 66% ≥college degree) completed questionnaires about caregiving context and sleep, then 10 prospectively-collected online daily sleep diaries. Caregivers then received access to SHUTi (Sleep Healthy Using the Internet), which has no caregiver-specific content, for 9 weeks, followed by post-assessment (questionnaires, diaries). Engagement was tracked by the SHUTi delivery system. RESULTS: Sixty caregivers completed SHUTi, 22 initiated but did not complete SHUTi, and 18 did not initiate SHUTi. Caregivers were more likely to use SHUTi (than not use SHUTi) when their care recipient (CR) had worse functioning, and were more likely to complete SHUTi when supporting more CR activities of daily living (ADL; ps < .03). Higher caregiver guilt, more CR problem behaviors, and being bedpartners with the CR related to more improved sleep outcomes, whereas supporting more CR instrumental ADL related to less improvement (ps < .05). CONCLUSIONS: Factors associated with greater caregiving burden, including greater CR impairment and caregiving guilt, were generally associated with better engagement and outcomes. Caregivers with substantial burdens can adhere to and benefit from a fully automated insomnia program without caregiver-specific tailoring.

This study examined how family caregivers, who often have trouble sleeping due to their responsibilities, used an online insomnia treatment program. The goal was to determine if certain aspects of caregiving would influence how caregivers engage with or benefit from the program. Researchers surveyed 100 caregivers with insomnia about their caregiving situation and sleep, and caregivers also kept online sleep diaries for 10 days. Afterward, caregivers used an online insomnia program with no caregiver-specific content called Sleep Healthy Using the Internet (SHUTi) for 9 weeks. Caregivers' usage was monitored, and they repeated measures of sleep outcomes and 10 online sleep diaries. Sixty caregivers completed SHUTi, 22 partially completed the program, and 18 did not initiate the program. Caregivers who cared for individuals with more severe functional limitations were more likely to use and complete SHUTi. Additionally, caregivers experiencing more guilt and those who managed more challenging behaviors from the person they cared for tended to report greater improvements in their sleep. This study suggests that caregivers, even those with significant care responsibilities, can use and benefit from an online insomnia treatment program like SHUTi, even when it has not been specifically tailored for caregivers.

Kids SIPsmartER reduces sugar-sweetened beverages among Appalachian middle-school students and their caregivers: a cluster randomized controlled trial.

BACKGROUND: High consumption of sugar-sweetened beverages (SSB) is a global health concern. Additionally, sugar-sweetened beverage (SSB) consumption is disproportionately high among adolescents and adults in rural Appalachia. The primary study objective is to determine the intervention effects of Kids SIPsmartER on students' SSB consumption. Secondary objectives focus on caregivers' SSB consumption and secondary student and caregiver outcomes [e.g, body mass index (BMI), quality of life (QOL)]. METHODS: This Type 1 hybrid, cluster randomized controlled trial includes 12 Appalachian middle schools (6 randomized to Kids SIPsmartER and 6 to control). Kids SIPsmartER is a 6-month, 12 lesson, multi-level, school-based, behavior and health literacy program aimed at reducing SSB among 7th grade middle school students. The program also incorporates a two-way text message strategy for caregivers. In this primary prevention intervention, all 7th grade students and their caregivers from participating schools were eligible to participate, regardless of baseline SSB consumption. Validated instruments were used to assess SSB behaviors and QOL. Height and weight were objectively measured in students and self-reported by caregivers. Analyses included modified two-part models with time fixed effects that controlled for relevant demographics and included school cluster robust standard errors. RESULTS: Of the 526 students and 220 caregivers, mean (SD) ages were 12.7 (0.5) and 40.6 (6.7) years, respectively. Students were 55% female. Caregivers were mostly female (95%) and White (93%); 25% had a high school education or less and 33% had an annual household income less than $50,000. Regardless of SSB intake at baseline and relative to control participants, SSB significantly decreased among students [-7.2 ounces/day (95% CI = -10.7, -3.7); p < 0.001, effect size (ES) = 0.35] and caregivers [-6.3 ounces/day (95% CI = -11.3, -1.3); p = 0.014, ES = 0.33]. Among students (42%) and caregivers (28%) who consumed > 24 SSB ounces/day at baseline (i.e., high consumers), the ES increased to 0.45 and 0.95, respectively. There were no significant effects for student or caregiver QOL indicators or objectively measured student BMI; however, caregiver self-reported BMI significantly decreased in the intervention versus control schools (p = 0.001). CONCLUSIONS: Kids SIPsmartER was effective at reducing SSB consumption among students and their caregivers in the rural, medically underserved Appalachian region. Importantly, SSB effects were even stronger among students and caregivers who were high consumers at baseline. TRIAL REGISTRATION: Clincialtrials.gov: NCT03740113. Registered 14 November 2018- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03740113 .

Short-peptide-based enteral nutrition affects rats MDP translocation and protects against gut-lung injury via the PepT1-NOD2-beclin-1 pathway in vivo.

BACKGROUND: Peptide transporter 1 (PepT1) transports bacterial oligopeptide products and induces inflammation of the bowel. Nutritional peptides compete for the binding of intestinal bacterial products to PepT1. We investigated the mechanism of short-peptide-based enteral nutrition (SPEN) on the damage to the gut caused by the bacterial oligopeptide product muramyl dipeptide (MDP), which is transported by PepT1. The gut-lung axis is a shared mucosal immune system, and immune responses and disorders can affect the gut-respiratory relationship. METHODS AND RESULTS: Sprague-Dawley rats were gavaged with solutions containing MDP, MDP + SPEN, MDP + intact-protein-based enteral nutrition (IPEN), glucose as a control, or glucose with GSK669 (a NOD2 antagonist). Inflammation, mitochondrial damage, autophagy, and apoptosis were explored to determine the role of the PepT1-nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-beclin-1 signaling pathway in the small intestinal mucosa. MDP and proinflammatory factors of lung tissue were explored to determine that MDP can migrate to lung tissue and cause inflammation. Induction of proinflammatory cell accumulation and intestinal damage in MDP gavage rats was associated with increased NOD2 and Beclin-1 mRNA expression. IL-6 and TNF-α expression and apoptosis were increased, and mitochondrial damage was severe, as indicated by increased mtDNA in the MDP group compared with controls. MDP levels and expression of proinflammatory factors in lung tissue increased in the MDP group compared with the control group. SPEN, but not IPEN, eliminated these impacts. CONCLUSIONS: Gavage of MDP to rats resulted in damage to the gut-lung axis. SPEN reverses the adverse effects of MDP. The PepT1-NOD2-beclin-1 pathway plays a role in small intestinal inflammation, mitochondrial damage, autophagy, and apoptosis.

Design, synthesis, and biological evaluation of N-(pyridin-3-yl)pyrimidin-4-amine analogues as novel cyclin-dependent kinase 2 inhibitors for cancer therapy.

The discovery and development of CDK2 inhibitors has currently been validated as a hot topic in cancer therapy. Herein, a series of novel N-(pyridin-3-yl)pyrimidin-4-amine derivatives were designed and synthesized as potent CDK2 inhibitors. Among them, the most promising compound 7l presented a broad antiproliferative efficacy toward diverse cancer cells MV4-11, HT-29, MCF-7, and HeLa with IC50 values of 0.83, 2.12, 3.12, and 8.61 µM, respectively, which were comparable to that of Palbociclib and AZD5438. Interestingly, these compounds were less toxic on normal embryonic kidney cells HEK293 with high selectivity index. Further mechanistic studies indicated 7l caused cell cycle arrest and apoptosis on HeLa cells in a concentration-dependent manner. Moreover, 7l manifested potent and similar CDK2/cyclin A2 nhibitory activity to AZD5438 with an IC50 of 64.42 nM. These findings revealed that 7l could serve as ahighly promisingscaffoldfor CDK2 inhibitors as potential anticancer agents and functional probes.

Clinical characteristics analysis of pediatric spinal cord injury without radiological abnormality in China: a retrospective study.

PURPOSE: This study aims to analyze the clinical characteristics of Chinese children with spinal cord injury (SCI) without radiographic abnormality (SCIWORA) and explore their contributing factors and mechanisms of occurrence. METHODS: A retrospective analysis was conducted on the clinical data of pediatric patients diagnosed with SCIWORA from January 2005 to May 2020. Epidemiological, etiological, mechanistic, therapeutic, and outcome aspects were analyzed. RESULTS: A total of 47 patients with SCIWORA were included in this study, comprising 16 males and 31 females. The age range was 4 to 12 years, with an average age of 7.49 ± 2.04 years, and 70% of the patients were below eight. Sports-related injuries constituted 66%, with 70% attributed to dance backbend practice. Thoracic segment injuries accounted for 77%. In the American Spinal Injury Association (ASIA) classification, the combined proportion of A and B grades accounted for 88%. Conservative treatment was chosen by 98% of the patients, with muscle atrophy, spinal scoliosis, hip joint abnormalities, and urinary system infections being the most common complications. CONCLUSION: SCIWORA in Chinese children is more prevalent in those under eight years old, with a higher incidence in females than males. Thoracic spinal cord injuries are predominant, dance backbend as a primary contributing factor, and the social environment of "neijuan" is a critical potential inducing factor. Furthermore, the initial severity of the injury plays a decisive role in determining the prognosis of SCIWORA.

Exploring Patterns and Disparities in E-Consult Referrals: An Analysis of Patient and Community Factors in Colorado Health Care.

Objective: Electronic consultations (e-consults) provide a strategic solution to address challenges in health care systems related to cost management and access to care. This study aims to investigate the multilevel patient characteristics associated with higher frequency of receiving e-consults and increased likelihood of completion. Materials and Methods: University of Colorado's electronic medical record were analyzed to study factors influencing referral types (e-consult vs. standard) and their completion rates from April 2018 to September 2023. Multivariate probit regression assessed the impact of patient-level and community-level factors (urban-rural classification, Social Vulnerability Index, and technology accessibility) on e-consult referrals and completion. Results: In 263,882 records, 92.5% were standard referrals, and 7.4% were e-consult referrals. Analysis showed that females were less likely than males (OR = 0.95, 95%CI[0.93, 0.96]), and Blacks were more likely than Whites (OR = 1.03, 95%CI[1.01,1.06]) to receive e-consult referrals. Medicaid patients had lower odds compared to those with Medicare only (OR = 1.04, 95%CI[1.00,1.07]), and rural residency was associated with lower odds (OR = 0.80, 95%CI[0.73,0.88]) of e-consult referral. Factors such as areas with higher population without internet subscription (OR = 1.03, 95%CI[1.01,1.04]) and higher social vulnerabilities (OR = 1.26, 95%CI[1.16,1.37]) increased e-consult odds. Black patients were less likely to have their referrals completed compared to Whites. Patients who resided in regions with limited computer and smartphone access, as well as higher social vulnerabilities, showed decreased odds of referral completion. Discussions and Conclusion: This study highlights the need for partnering with a variety of health care organizations, especially those serving low-income and disadvantaged populations, to enhance health care access equity through the use of e-consults.

Decoding Cosmetic Complexities: A Comprehensive Guide to Matrix Composition and Pretreatment Technology.

Despite advancements in analytical technologies, the complex nature of cosmetic matrices, coupled with the presence of diverse and trace unauthorized additives, hinders the application of these technologies in cosmetics analysis. This not only impedes effective regulation of cosmetics but also leads to the continual infiltration of illegal products into the market, posing serious health risks to consumers. The establishment of cosmetic regulations is often based on extensive scientific experiments, resulting in a certain degree of latency. Therefore, timely advancement in laboratory research is crucial to ensure the timely update and adaptability of regulations. A comprehensive understanding of the composition of cosmetic matrices and their pretreatment technologies is vital for enhancing the efficiency and accuracy of cosmetic detection. Drawing upon the China National Medical Products Administration's 2021 Cosmetic Classification Rules and Classification Catalogue, we streamline the wide array of cosmetics into four principal categories based on the following compositions: emulsified, liquid, powdered, and wax-based cosmetics. In this review, the characteristics, compositional elements, and physicochemical properties inherent to each category, as well as an extensive overview of the evolution of pretreatment methods for different categories, will be explored. Our objective is to provide a clear and comprehensive guide, equipping researchers with profound insights into the core compositions and pretreatment methods of cosmetics, which will in turn advance cosmetic analysis and improve detection and regulatory approaches in the industry.

Prefrontal GABAA(δ)R Promotes Fear Extinction through Enabling the Plastic Regulation of Neuronal Intrinsic Excitability.

Extinguishing the previously acquired fear is critical for the adaptation of an organism to the ever-changing environment, a process requiring the engagement of GABAA receptors (GABAARs). GABAARs consist of tens of structurally, pharmacologically, and functionally heterogeneous subtypes. However, the specific roles of these subtypes in fear extinction remain largely unexplored. Here, we observed that in the medial prefrontal cortex (mPFC), a core region for mood regulation, the extrasynaptically situated, δ-subunit-containing GABAARs [GABAA(δ)Rs], had a permissive role in tuning fear extinction in male mice, an effect sharply contrasting to the established but suppressive role by the whole GABAAR family. First, the fear extinction in individual mice was positively correlated with the level of GABAA(δ)R expression and function in their mPFC. Second, knockdown of GABAA(δ)R in mPFC, specifically in its infralimbic (IL) subregion, sufficed to impair the fear extinction in mice. Third, GABAA(δ)R-deficient mice also showed fear extinction deficits, and re-expressing GABAA(δ)Rs in the IL of these mice rescued the impaired extinction. Further mechanistic studies demonstrated that the permissive effect of GABAA(δ)R was associated with its role in enabling the extinction-evoked plastic regulation of neuronal excitability in IL projection neurons. By contrast, GABAA(δ)R had little influence on the extinction-evoked plasticity of glutamatergic transmission in these cells. Altogether, our findings revealed an unconventional and permissive role of extrasynaptic GABAA receptors in fear extinction through a route relying on nonsynaptic plasticity.SIGNIFICANCE STATEMENT The medial prefrontal cortex (mPFC) is one of the kernel brain regions engaged in fear extinction. Previous studies have repetitively shown that the GABAA receptor (GABAAR) family in this region act to suppress fear extinction. However, the roles of specific GABAAR subtypes in mPFC are largely unknown. We observed that the GABAAR-containing δ-subunit [GABAA(δ)R], a subtype of GABAARs exclusively situated in the extrasynaptic membrane and mediating the tonic neuronal inhibition, works oppositely to the whole GABAAR family and promotes (but does not suppress) fear extinction. More interestingly, in striking contrast to the synaptic GABAARs that suppress fear extinction by breaking the extinction-evoked plasticity of glutamatergic transmission, the GABAA(δ)R promotes fear extinction through enabling the plastic regulation of neuronal excitability in the infralimbic subregion of mPFC. Our findings thus reveal an unconventional role of GABAA(δ)R in promoting fear extinction through a route relying on nonsynaptic plasticity.

Examining Smoking Prevalence Disparities in Virginia Counties by Rurality, Appalachian Status, and Social Vulnerability, 2011-2019.

Objectives. To estimate county-level cigarette smoking prevalence in Virginia and examine cigarette use disparities by rurality, Appalachian status, and county-level social vulnerability. Methods. We used 2011-2019 Virginia Behavioral Risk Factor Surveillance System proprietary data with geographical information to estimate county-level cigarette smoking prevalence using small area estimation. We used the Centers for Disease Control and Prevention's social vulnerability index to quantify social vulnerability. We used the 2-sample statistical t test to determine the differences in cigarette smoking prevalence and social vulnerability between counties by rurality and Appalachian status. Results. The absolute difference in smoking prevalence was 6.16 percentage points higher in rural versus urban counties and 7.52 percentage points higher in Appalachian versus non-Appalachian counties in Virginia (P < .001). Adjusting for county characteristics, a higher social vulnerability index is associated with increased cigarette use. Rural Appalachian counties had 7.41% higher cigarette use rates than did urban non-Appalachian areas. Tobacco agriculture and a shortage of health care providers were significantly associated with higher cigarette use prevalence. Conclusions. Rural Appalachia and socially vulnerable counties in Virginia have alarmingly high rates of cigarette use. Implementation of targeted intervention strategies could reduce cigarette use, ultimately reducing tobacco-related health disparities. (Am J Public Health. 2023;113(7):811-814. https://doi.org/10.2105/AJPH.2023.307298).

Preschool- and childcare center-based interventions to increase fruit and vegetable intake in preschool children in the United States: a systematic review of effectiveness and behavior change techniques.

BACKGROUND: Fruit and vegetable (FV) consumption in children in the United States (US) is very low. Adequate FV consumption is required for proper development during childhood, and dietary habits are established during preschool-age and tend to persist into adulthood. As most U.S. preschool-aged children attend childcare or preschool, this may be an opportune time and setting to conduct interventions to improve FV intake. These interventions should be based in theory and use behavior change techniques (BCTs) to explain mechanisms for expected change. To date, no published reviews have examined the effectiveness of childcare- or preschool-based FV interventions in preschoolers and their use of theoretical frameworks and BCTs. METHODS: This systematic review was completed adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria were randomized controlled trials (RCTs) published between 2012 and 2022 of interventions to improve diet or FV intake in preschoolers (aged 2-5 years) in childcare or preschool-settings. A search of four databases was conducted between in September 2022 using search terms pertaining to the study's primary aim (FV consumption), age group (preschool-aged), settings (US childcare or preschool settings), and study design (RCT). Additional criteria were objective measures of FV consumption or skin carotenoids, as a proxy for FV intake. Included studies were narratively synthesized based on intervention type, measured effect, and use of theory and BCTs. RESULTS: The search resulted in six studies that reported on nine interventions. Overall, six interventions increased FV intake, of which five used nutrition education and one manipulated the feeding environment. Among the three interventions with no measured effect, two manipulated the feeding environment and one used peer modeling. Effective studies used at least three BCTs, though no pattern was observed between use of theory or BCTs and intervention effect. CONCLUSIONS: While several studies have shown promising results, the limited number of studies identified in this review highlights key gaps in this field: there is a need for studies to test FV interventions in US childcare settings that use objective measures of FV intake, directly compare intervention components and BCTs, are theory-based, and assess long-term behavior change.

Oxygen defect-mediated NiCo2O4 nanosheets as the electrode for pseudocapacitors with improved rate capability.

Transition metal oxide-based supercapacitors have attracted much attention due to their high theoretical specific capacitances. However, due to an insufficient utilization ratio and poor intrinsic conductivity of active materials, the rate performance of these electrodes is usually low. Herein, oxygen defect-mediated NiCo2O4 nanosheets with enhanced electrical conductivity (1.9 S m-1vs. 0.2 S m-1 of original NiCo2O4 NSs) are fabricated using a post NaBH4 reduction strategy (denoted as r-NiCo2O4 NSs). The derived r-NiCo2O4 materials have sheet-like morphology, increased oxygen defects and low valence metal species, and an unprecedented rate capability comparable to that of carbon-based electrode materials, with a satisfactory capacitance of 1812 F g-1 and 91.5% retention at 20 A g-1. The general strategy can be extended to other transition metal oxides to construct enhanced conductivity electrodes for related energy storage and conversion devices.

Bcl2l1 Deficiency in Osteoblasts Reduces the Trabecular Bone Due to Enhanced Osteoclastogenesis Likely through Osteoblast Apoptosis.

Bcl2l1 (Bcl-XL) belongs to the Bcl-2 family, Bcl2 and Bcl2-XL are major anti-apoptotic proteins, and the apoptosis of osteoblasts is a key event for bone homeostasis. As the functions of Bcl2l1 in osteoblasts and bone homeostasis remain unclear, we generated osteoblast-specific Bcl2l1-deficient (Bcl2l1fl/flCre) mice using 2.3-kb Col1a1 Cre. Trabecular bone volume and the trabecular number were lower in Bcl2l1fl/flCre mice of both sexes than in Bcl2l1fl/fl mice. In bone histomorphometric analysis, osteoclast parameters were increased in Bcl2l1fl/flCre mice, whereas osteoblast parameters and the bone formation rate were similar to those in Bcl2l1fl/fl mice. TUNEL-positive osteoblastic cells and serum TRAP5b levels were increased in Bcl2l1fl/flCre mice. The deletion of Bcl2l1 in osteoblasts induced Tnfsf11 expression, whereas the overexpression of Bcl-XL had no effect. In a co-culture of Bcl2l1-deficient primary osteoblasts and wild-type bone-marrow-derived monocyte/macrophage lineage cells, the numbers of multinucleated TRAP-positive cells and resorption pits increased. Furthermore, serum deprivation or the deletion of Bcl2l1 in primary osteoblasts increased apoptosis and ATP levels in the medium. Therefore, the reduction in trabecular bone in Bcl2l1fl/flCre mice may be due to enhanced bone resorption through osteoblast apoptosis and the release of ATP from apoptotic osteoblasts, and Bcl2l1 may inhibit bone resorption by preventing osteoblast apoptosis.

Effectiveness of incentives to improve the reach of health promotion programs- a systematic review and meta-analysis.

The reach (i.e., enrollment, engagement, and retention) of health promotion evidence-based programs (EBPs) at the participant level has been challenging. Incentives based on behavioral economics may be used to improve EBP reach. We aimed to systematically review and synthesize the evidence of the effectiveness of incentives as a dissemination strategy to increase EBP reach. We conducted a literature search in PubMed, SCOPUS, EMBASE, Cochrane Review and Cochrane CENTRAL for articles published between January 2000 and March 2020 to identify incentive strategies used to increase program reach among health promotion EBPs. Inclusion criteria included studies published in English, experimental or quasi-experimental designs, comparison of incentive to non-incentive or control strategies, and reported on reach (n = 35 health promotion studies). Monetary incentives using cash and a fixed schedule of reinforcement were the most used incentive schemes (71%). Incentives alone or combined with other strategies as a multicomponent approach were effective in improving program enrollment, engagement, and retention. Specifically, incentive strategies were associated with higher odds of program enrollment (odds ratio [OR], 2.78; 95% confidence interval [CI], 1.82-4.24; n = 10) and retention (OR, 2.54, 95% CI, 1.34-4.85; n = 9) with considerable heterogeneity (I2 = 94% and 91%, respectively). Incentives are a promising individual-level dissemination strategy to improve the reach of health promotion EBPs. However, understanding the optimal amount, type, frequency, and target of incentives, and how incentives fit in a multicomponent approach in different contexts requires further research.

Concise synthesis and preliminary biological evaluation of new triazolylthioacetone derivatives bearing pyridine, pyrazine, and 3,4,5-trimethoxybenzyl fragment.

Based on our previous work, a series of novel triazolylthioacetones incorporating pyridine, pyrazine, and 3,4,5-trimethoxybenzyl fragment were synthesized, and evaluated for antiproliferative activities and interactions with tubulin. Some analogues exhibited moderate to excellent potency, with the most promising compound IIc possessing IC50 values of 0.62, 1.46, and 3.65 µM against HT-29, HCT116, and HepG2 tumor cells, respectively, which were comparable with the positive control CA-4. Mechanistical studies revealed that IIc concentration-dependently caused cell cycle arrest at the G2/M phase in HCT116 tumor cells, and displayed a significant inhibition of tubulin polymerization with an IC50 value of 12.7 µM. Moreover, molecular docking analysis suggested that IIc could occupy the colchicine-binding site in a similar way with typical tubulinpolymerizationinhibitors. These results highlighted the 4-amino-triazolylthioacetone scaffold as potential tubulin polymerization inhibitors for development of highly efficient anticancer agents.