Comparison of Researcher-Led versus Teacher-Led effectiveness and fidelity: A Hybrid Type 1 study of Kids SIPsmartER in Appalachia middle schools.

The implementation of school-based obesity-prevention programs is understudied. Kids SIPsmartER is a 6-month, school-based, behavioral intervention for Appalachian middle school students and includes a teacher implementation strategy. Kids SIPsmartER effectively reduced students' sugar-sweetened beverages (SSB) when Researcher-Led. However, Teacher-Led effectiveness and fidelity are unknown. To explore the relative SSB effects when Kids SIPsmartER was Researcher-Led versus Teacher-Led and to examine teacher fidelity. This study of secondary outcomes used a quasi-experimental analytic approach of a Hybrid Type 1 effectiveness-implementation and cluster randomized controlled tria (RCT) of Kids SIPsmartER. Student SSB behaviors and teacher self-rated fidelity were assessed, respectively, with the validated Beverage Intake Questionnaire (BEVQ-15) and lesson-specific checklists. Analyses included descriptive statistics and modified two-part models with time-fixed effects and school-year cohort cluster controls. The analytic sample included students from six control schools (n = 220), six Researcher-Led intervention schools (n = 306), and five Teacher-Led intervention schools (n = 218), as well as eight teachers. Teacher-Led intervention students decreased SSB by -14.3 ounces/day (95% confidence interval = -15.4, -13.2; P < .001). Relative to control and to Researcher-Led intervention, the Teacher-Led treatment effect among students was -11.6 ounces SSB/day (P < .001, effect size = 0.75) and -4.3 (P = .004, effect size = 0.25), respectively. Teachers returned fidelity checklists for 90% of planned lessons. Fidelity averaged 94% (SD = 4.0%) among returned forms and 85% (SD = 18.9%) when missing forms were counted as zeros. Teachers can implement Kids SIPsmartER with high fidelity and produce statistically and clinically meaningful improvements in students' SSB behaviors. Findings have implications for the sustained implementation of Kids SIPsmartER and other school-based obesity-prevention programs. Clinical Trial information: NCT03740113.

Numerous evidence-based behavioral interventions related to obesity prevention have been established in schools, yet relatively few have been replicated or successfully implemented by teachers. Kids SIPsmartER is a school-based, behavioral intervention for Appalachian middle school students that effectively reduced students' sugar-sweetened beverages (SSB) when delivered by researchers. This study describes the implementation strategies bundle for teachers. The purpose of this study was to explore SSB effects among students when Kids SIPsmartER was delivered by teachers versus delivered by researchers and relative to control students. Teacher fidelity to the program was also examined. Students decreased their SSB more when teachers delivered Kids SIPsmartER, compared with when the researcher delivered the program and to control students. Teachers also taught the intervention with high program fidelity. In sum, teachers can implement Kids SIPsmartER with high fidelity and can produce meaningful improvements in students' SSB behaviors. Findings have implications for the sustained implementation of Kids SIPsmartER among teachers as well as for other school-based programs.

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.

Vonoprazan-amoxicillin dual therapy for Helicobacter pylori eradication in Chinese population: A prospective, multicenter, randomized, two-stage study.

BACKGROUND: The efficacy of Vonoprazan-amoxicillin dual therapy (VAT) in the treatment of Helicobacter pylori (H. pylori) is controversial. AIM: To evaluate the efficacy of VAT in the Chinese population. METHODS: This prospective, multicenter, randomized, open-label, and two-stage study was conducted at 23 centers in Fujian, China (May 2021-April 2022). H. pylori-infected patients were randomized to bismuth quadruple therapy (BQT), BQT-Vonoprazan (BQT-V), seven-day VAT (VAT-7), ten-day VAT (VAT-10), and fourteen-day VAT (VAT-14) groups. The primary endpoint was the H. pylori eradication rate. The secondary endpoint was the frequency of adverse events. This study was registered with the Chinese Clinical Trial Registry, ChiCTR2100045778. RESULTS: In the first stage, VAT-7 and BQT-V groups were selected for early termination because less than 23 among 28 cases were eradicated. In the second stage, the eradication rates for BQT, VAT-10, and VA-14 were 80.2% [95% confidence interval (95%CI): 71.4%-86.8%], 93.2% (86.6%-96.7%), 92.2% (85.3%-96.0%) in the intention-to-treat (ITT) analysis, and 80.9% (95%CI: 71.7%-87.5%), 94.0% (87.5%-97.2%), and 93.9% (87.4%-97.2%) in the per-protocol analysis. The ITT analysis showed a higher eradication rate in the VAT-10 and VAT-14 groups than in the BQT group (P = 0.022 and P = 0.046, respectively). The incidence of adverse events in the VAT-10 and VAT-14 groups was lower than in the BQT group (25.27% and 13.73% vs 37.62%, respectively; P < 0.001). CONCLUSION: VAT with a duration of 10 or 14 days achieves a higher eradication rate than the BQT, with a more tolerable safety profile in H. pylori-infected patients in Fujian.

Association Between Medicare Site-Based Payment Policy, Physician Practice Characteristics, and Vertical Integration Among Oncologists.

PURPOSE: Medicare's differential payments for services delivered in physician offices versus hospital outpatient settings incentivize hospital-physician integration (ie, vertical integration) across many specialties, but evidence for oncologists is mixed. We examined the association of Medicare site-based payment policy and physician practice characteristics, including service volume and diversity, with vertical integration among oncologists in 2013-2019. METHODS: Using the Medicare Provider Utilization and Payment Data and Medicare Data on Provider Practice and Specialty in 2013-2019, we extracted nonintegrated medical/hematologic oncologists (hereafter oncologists) in 2013 and followed them through 2019. We quantified the incentives from Medicare site-based payment policy using the hospital-office ratio-total Medicare payments if all services were delivered in the hospital outpatient department (HOPD) versus physician office. Vertical integration was defined as billing >10% of services to HOPD in a year. Multivariable linear probability regressions estimated the association between hospital-office ratio and vertical integration in 2014-2019 with and without accounting for provider characteristics. RESULTS: In 2013, the average hospital-office ratio was 1.63, which increased to 1.99 in 2018. A 25th-to-75th percentile increase in the hospital-office ratio was negatively associated with integration (-1.01 percentage points [ppts], 95% CI = -1.45 to -0.57, p < .001) not accounting for physician practice characteristics; this association was attenuated (-0.30 ppts, 95% CI = -0.67 to 0.07, p = .11) after adjusting for these characteristics. Higher baseline (ie, 2013) service volume (Quartile4 v Quartile1 = -3.00 ppts, 95% CI = -4.42 to -1.59, p < .001), more diverse services (Quartile4 v Quartile1 = -3.55 ppts, 95% CI = -4.97 to -2.13, p < .001), and urban location (-5.23 ppts, 95% CI = -6.89 to -3.57, p < .001) were more strongly associated with vertical integration. CONCLUSION: Compared to Medicare site-based payment policy, oncologists' practice characteristics emerged as more potent factors for integration and should be considered to ensure the intended impacts of site-based payment reform. Our finding raises questions about the effectiveness of ongoing movements toward site-neutral payment for drug administration services to deter vertical integration in oncology.

Unveiling rural and Appalachian disparities in cigarette smoking through the social vulnerability index and other county-level characteristics.

PURPOSE: Mitigating tobacco-related disparities in the Appalachian region and rural areas is crucial. This study seeks to gauge cigarette smoking prevalence in Virginia counties, uncover rurality and Appalachian-linked disparities, and explore local drivers of these gaps. METHOD: A 2011-2019 Virginia BRFSS data were used to estimate county-level cigarette smoking rates in adults aged 18 or older. Counties were categorized as urban/rural and Appalachian/non-Appalachian, with a focus on rural-Appalachian. Disparities in cigarette smoking rates and associated factors were analyzed via the Blinder-Oaxaca decomposition method. The study assessed 4 dimensions of the Centers for Disease Control and Prevention's social vulnerability index (SVI): socioeconomic, minority status, household composition, and housing. Additionally, county-specific factors such as tobacco agriculture, physician availability, coal mining, and tobacco retailer density were examined. FINDINGS: Rural areas exhibited a 6.18% higher cigarette smoking prevalence compared to urban areas (P<.001). SVI dimensions accounted for 53.2% of the disparity, county features explained 16.4%, and 30.4% remained unexplained. Appalachian areas had a 6.79% higher cigarette smoking prevalence than non-Appalachian areas (P<.001). SVI dimensions explained 51.4% of the disparity, county features accounted for 21.8%, leaving 26.8% unexplained. Rural-Appalachian areas showed a 7.8% higher cigarette smoking prevalence (P<.001). SVI dimensions contributed to 51.7% of the disparity, county features explained 9.6%, and 38.7% remained unexplained. CONCLUSIONS: Substantial disparities in cigarette smoking prevalence exist in underserved areas of Virginia, including rural, Appalachian, and rural-Appalachian regions. While SVI dimensions, physician availability, tobacco agriculture, and coal mining contribute, yet notable gaps remain unexplained. Targeted interventions must tackle unique challenges in disadvantaged areas to reduce smoking and promote health equity.

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.

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.

Toxic epidermal necrolysis caused by viral hepatitis A: a case report and literature review.

Toxic epidermal necrolysis (TEN) is a rare but serious immune-mediated life-threatening skin and mucous membrane reaction that is mainly caused by drugs, infections, vaccines, and malignant tumors. A 74-year-old woman presented with a moderate fever of unknown cause, which was relieved after 2 days, but with weakness and decreased appetite. Red maculopapules appeared successively on the neck, trunk, and limbs, expanding gradually, forming herpes and fusion, containing a yellow turbidous liquid and rupturing to reveal a bright red erosive surface spreading around the eyes and mouth. The affected body surface area was >90%. The severity of illness score for toxic epidermal necrolysis was 2 points. The drug eruption area and severity index score was 77. She was diagnosed with TEN caused by hepatitis A virus and treated with 160 mg/day methylprednisolone, 300 mg/day cyclosporine, and 20 g/day gammaglobulin. Her skin showed improvements after 3 days of treatment and returned to nearly normal after 1 month, and liver function was completely normal after 2 months.

Pathologic assessment of hepatocellular carcinoma in the era of immunotherapy: a narrative review.

Background and Objective: Immune checkpoint inhibitor (ICI)-based therapy has achieved impressive success in various cancer types. Several ICIs have been unprecedentedly approved as the treatment regimens for advanced hepatocellular carcinoma (HCC) in recent decade. Meanwhile, numerous clinical trials are being performed to exploit more ICIs into initially unresectable HCC and postoperative HCC to expectantly induce adequate tumor downstaging for further resection or implement adjuvant treatment for relapse-free survival, respectively. In this review, we aim to summarize some pragmatic histomorphologic, immunohistochemical, and molecular pathologic parameters which promisingly indicate the response of neoadjuvant/conversion ICI-related therapy and predict the efficacy of adjuvant/therapeutic ICI-related therapy for HCC. Methods: We searched PubMed using the terms hepatocellular carcinoma, immunotherapy, immune checkpoint inhibitor, immune checkpoint blockade, conversion therapy, neoadjuvant therapy, adjuvant therapy, biomarker, pathologic evaluation, pathologic assessment till February 2023. Key Content and Findings: Although there is no consensus regarding the pathologic evaluation of relevant HCC specimens, it is encouraging that a few of studies have concentrated on this field, and moreover, the methods and parameters noted on other cancer types are also worthy of reference. For the pathologic assessment of HCC specimens underwent immunotherapy, a suitable sampling scheme, identifying immunotherapy-related pathologic response, and quantification of pathologic response rate should be emphasized. For the patients of HCC who are scheduled to receive immunotherapy, tumor-infiltrating lymphocyte, intratumoral tertiary lymphoid structure, programmed cell death ligand 1, Wnt/ß-catenin, microsatellite instability and mismatch repair, tumor mutational burden and tumor neoantigen, as well as some other signaling pathways are the potential predictive biomarkers of treatment response of ICI. Conclusions: The management of HCC in the era of immunotherapy arises a brand-new pathological challenge that is to provide an immunotherapy-related diagnostic report. Albeit many related researches are preclinical or insufficient, they may tremendously alter the immunotherapy strategy of HCC in future.

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.

Quantum criticality of generalized Aubry-André models with exact mobility edges using fidelity susceptibility.

In this study, we explore the quantum critical phenomena in generalized Aubry-André models, with a particular focus on the scaling behavior at various filling states. Our approach involves using quantum fidelity susceptibility to precisely identify the mobility edges in these systems. Through a finite-size scaling analysis of the fidelity susceptibility, we are able to determine both the correlation-length critical exponent and the dynamical critical exponent at the critical point of the generalized Aubry-André model. Based on the Diophantine equation conjecture, we can determines the number of subsequences of the Fibonacci sequence and the corresponding scaling functions for a specific filling fraction, as well as the universality class. Our findings demonstrate the effectiveness of employing the generalized fidelity susceptibility for the analysis of unconventional quantum criticality and the associated universal information of quasiperiodic systems in cutting-edge quantum simulation experiments.

High performance molecular iodine optical reference using an unsaturated vapor cell.

We describe a high-performance molecular iodine optical frequency reference that is referenced to the R(56)32-0: a1 hyperfine transition of molecular iodine based on modulation transfer spectroscopy. We design an unsaturated iodine vapor cell with a gas pressure equivalent to the saturation pressure at -17 °C. Using this cell, we developed a compact, frequency-stabilized laser. The iodine cell operates at room temperature and is not actively temperature stabilized. We demonstrate a laser with fractional frequency instability of 1.4 × 10-14 at 1 s and 1.7 × 10-15 at 104 s. To our knowledge, the level of frequency instability at 104 s is comparable to the previously reported best results for an iodine stabilized laser. These results suggest that using an unsaturated iodine vapor cell is a valid approach for the development of long-term, stable iodine-based optical references.

Activation of pyramidal neurons in the infralimbic cortex alleviates LPS-induced depressive-like behavior in mice.

The infralimbic (IL) cortex dysfunction has been implicated in major depressive disorder (MDD), yet the precise cellular and molecular mechanisms remain poorly understood. In this study, we investigated the role of layer V pyramidal neurons in a mouse model of MDD induced by repeated lipopolysaccharide (LPS) administration. Our results demonstrate that three days of systemic LPS administration induced depressive-like behavior and upregulated mRNA levels of interleukin-1ß (IL-1ß), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-ß (TGF-ß) in the IL cortex. Electrophysiological recordings revealed a significant decrease in the intrinsic excitability of layer V pyramidal neurons in the IL following systemic LPS exposure. Importantly, chemogenetic activation of IL pyramidal neurons ameliorated LPS-induced depressive-like behavior. Additionally, LPS administration significantly increased microglial activity in the IL, as evidenced by a greater number of Ionized calcium binding adaptor molecule-1 (IBA-1)-positive cells. Morphometric analysis further unveiled enlarged soma, decreased branch numbers, and shorter branch lengths of microglial cells in the IL cortex following LPS exposure. Moreover, the activation of pyramidal neurons by clozapine-N-oxide increased the microglia branch length but did not change branch number or cytosolic area. These results collectively suggest that targeted activation of pyramidal neurons in the IL cortex mitigates microglial response and ameliorates depressive-like behaviors induced by systemic LPS administration. Therefore, our findings offer potential therapeutic targets for the development of interventions aimed at alleviating depressive symptoms by modulating IL cortical circuitry and microglial activity.

Clinical efficacy of CDK4/6 inhibitor plus endocrine therapy in HR-positive/HER2-0 and HER2-low-positive metastatic breast cancer: a secondary analysis of PALOMA-2 and PALOMA-3 trials.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with traditional endocrine therapy (ET) are now the recommended first-line treatment for hormone receptor (HR)-positive and HER2-negative metastatic breast cancer (MBC). However, the benefits of adding CDK4/6 inhibitors to ET in HER2-low-positive and HER2-0 subgroups remain unclear. We aimed to assess the effectiveness of CDK4/6 inhibitors in combination with ET in patients with HR-positive, HER2-low-positive and HER2-0 MBC. METHODS: This secondary analysis assessed progression-free survival (PFS) among HER2-low-positive and HER2-0 patients enrolled in the double-blind, placebo-controlled randomised clinical trials PALOMA-2 and PALOMA-3. The study included 1186 HER2-negative, HR-positive female patients, with available immunohistochemistry (IHC) and/or in situ hybridization (ISH) results, across 17 countries enrolled between February 2013 and August 2014. HER2-low-positive status was defined by IHC 1+ or 2+ with negative ISH, and HER2-zero by IHC 0. Data analyses were conducted between March and May 2023. In the PALOMA-2 trial, patients were randomly assigned to receive either palbociclib or placebo, in combination with letrozole in the first-line treatment for HR-positive MBC. Patients in the PALOMA-3 study, who had progression or relapse during previous ET, were randomly allocated to receive either palbociclib plus fulvestrant or placebo plus fulvestrant. The primary endpoint was investigator-assessed PFS. Kaplan-Meier approach and Cox proportional hazards model were applied to estimate the association of treatment strategies with PFS among HER2-0 and HER2-low-positive populations. The two trials are registered with ClinicalTrials.gov, number NCT01740427 and NCT01942135. FINDINGS: Of the 666 patients with MBC from the PALOMA-2 study, there were 153 HER2-0 and 513 HER2-low-positive patients. In the HER2-0 population, no significant difference in PFS was observed between the palbociclib-letrozole and placebo-letrozole groups (hazard ratio = 0.79, 95% confidence interval [CI] 0.48-1.30, p = 0.34). In the HER2-low-positive population, palbociclib-letrozole demonstrated a significantly lower risk of PFS than placebo-letrozole group (hazard ratio = 0.52, 95% CI 0.41-0.66, p < 0.0001). The PALOMA-3 study analysed 520 patients with MBC. Within the 153 HER2-0 patients, the palbociclib-fulvestrant group showed a significantly longer PFS than the placebo-fulvestrant group (hazard ratio = 0.54, 95% CI 0.30-0.95, p = 0.034). Among the 367 HER2-low-positive patients, palbociclib-fulvestrant improved PFS (hazard ratio = 0.39, 95% CI 0.28-0.54, p < 0.0001). INTERPRETATION: The combination of a CDK4/6 inhibitor with ET significantly improved PFS in HER2-low-positive patients, while for HER2-0 patients, benefits were primarily observed in patients who had progressed on previous ET. Furthermore, HER2-0 patients may derive limited benefits from first-line CDK4/6 inhibitor treatment. Further work is needed to validate these findings and to delineate patient subsets that are most likely to benefit from the combination of CDK4/6 inhibitors and ET as first-line treatments. FUNDING: None.

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.

Growth and physiological responses of submerged macrophytes to linear alkylbenzene sulfonate (LAS).

The potential toxic effects of linear alkylbenzene sulfonate (LAS), widely used in commercial detergents and cleaners, on submerged macrophytes remain unclear. We conducted a two-week exposure experiment to investigate LAS toxicity on five submerged macrophytes (four native and one exotic), focusing on their growth and physiological responses. The results showed that lower concentrations of LAS (< 5 mg/L) slightly stimulated the growth of submerged macrophytes, while higher doses inhibited it. Increasing LAS concentration resulted in decreased chlorophyll content, increased MDA content and POD activity, and initially increased SOD and CAT activities before declining. Moreover, Elodea nuttallii required a higher effective concentration for growth compared to native macrophytes. These findings suggest that different species of submerged macrophytes exhibited specific responses to LAS, with high doses (exceeding 5 ∼ 10 mg/L) inhibited plant growth and physiology. However, LAS may promote the dominance of surfactant-tolerant exotic submerged macrophytes in polluted aquatic environments.

Overweight/obesity, gestational weight gain, postpartum weight retention, and maternal/neonatal complications in the military.

OBJECTIVE: The objective of this study was to examine the prevalence of overweight/obesity and excessive gestational weight gain (GWG) among military beneficiaries and to assess associations of these risk factors with maternal/neonatal complications and substantial postpartum weight retention (PPWR). METHODS: We obtained data for 48,391 TRICARE beneficiaries who gave birth in 2018 or 2019 in the United States. We used logistic regression and ANOVA to examine relationships among overweight/obesity, GWG, maternal/neonatal complications, and substantial PPWR. RESULTS: Most TRICARE beneficiaries (75%) had excessive GWG, and 42% had substantial PPWR. Dependents were less likely than active-duty women to have excessive GWG (odds ratio [OR] = 0.73, 95% CI: 0.60-0.88). Women with excessive GWG were three times more likely to have substantial PPWR (OR = 3.57, 95% CI: 3.14-4.06). Those with excessive GWG were more likely to have maternal/neonatal complications (e.g., pregnancy-induced hypertension, cesarean delivery). CONCLUSIONS: Excessive GWG is frequent among TRICARE beneficiaries, particularly active-duty personnel, and is strongly associated with costly maternal/neonatal complications. Substantial PPWR is also common in this population, with excessive GWG as a key risk factor.

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.

Chlorogenic Acid Intravesical Therapy Changes Acute Voiding Behavior of Systemic Lipopolysaccharide Inflammation-Induced Cystitis Bladder in Mice.

This study explores the potential efficacy of chlorogenic acid (CGA) in mitigating lipopolysaccharide (LPS)-induced cystitis in a mice model. C57BL/6J mice were divided into four groups: normal control (NC), LPS, LPS + low CGA, and LPS + high CGA. Evaluation methods included cystometrogram (CMG), histopathological, western blot, and immunohistological analysis. In the LPS group, CMG revealed abnormal voiding behavior with increased micturition pressure, voided volume (VV), and decreased voided frequency. Low CGA treatment in LPS mice demonstrated improved micturition pressure and inter-contraction intervals (ICI). However, high CGA treatment exhibited prolonged ICI and increased VV, suggesting potential adverse effects. Histological analysis of LPS-treated mice displayed bladder inflammation and interstitial edema. Low CGA treatment reduced interstitial edema and bladder inflammation, confirmed by Masson's trichrome staining. Western blotting revealed increased cytokeratin 20 (K20) expression in the low CGA group, indicating structural abnormalities in the bladder umbrella layer after LPS administration. In conclusion, low CGA treatment positively impacted voiding behavior and decreased bladder edema and inflammation in the LPS-induced cystitis mice model, suggesting its potential as a supplement for inflammation cystitis prevention. However, high CGA treatment exhibited adverse effects, emphasizing the importance of dosage considerations in therapeutic applications.

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 .