The Mediating Role of Cortical Atrophy on the Relationship between the Resilience Index and Cognitive Function: Findings from the Healthy Brain Initiative.

Background: Lifestyle factors are linked to differences in brain aging and risk for Alzheimer's disease, underscored by concepts like 'cognitive reserve' and 'brain maintenance'. The Resilience Index (RI), a composite of 6 factors (cognitive reserve, physical and cognitive activities, social engagement, diet, and mindfulness) provides such a holistic measure. Objective: This study aims to examine the association of RI scores with cognitive function and assess the mediating role of cortical atrophy. Methods: Baseline data from 113 participants (aged 45+, 68% female) from the Healthy Brain Initiative were included. Life course resilience was estimated with the RI, cognitive performance with Cognivue®, and brain health using a machine learning derived Cortical Atrophy Score (CAS). Mediation analysis probed the relationship between RI, cognitive outcomes, and cortical atrophy. Results: In age and sex adjusted models, the RI was significantly associated with CAS (ß= -0.25, p = 0.006) and Cognivue® scores (ß= 0.32, p < 0.001). The RI-Cognivue® association was partially mediated by CAS (ß= 0.07; 95% CI [0.02, 0.14]). Conclusions: Findings revealed that the collective effect of early and late-life lifestyle resilience factors on cognition are partially explained by their association with less brain atrophy. These findings underscore the value of comprehensive lifestyle assessments in understanding the risk and progression of cognitive decline and Alzheimer's disease in an aging population.

Extracellular matrix degrading enzyme with stroma-targeting peptides enhance the penetration of liposomes into tumors.

Various anti-tumor nanomedicines have been developed based on the enhanced permeability and retention effect. However, the dense extracellular matrix (ECM) in tumors remains a major barrier for the delivery and accumulation of nanoparticles into tumors. While ECM-degrading enzymes, such as collagenase, hyaluronidase, and bromelain, have been used to facilitate the accumulation of nanoparticles, serious side effects arising from the current non-tumor-specific delivery methods limit their clinical applications. Here, we report targeted delivery of bromelain into tumor tissues through its covalent attachment to a hyaluronic acid (HA)-peptide conjugate with tumor ECM targeting ability. The ECM targeting peptide, collagen type IV-binding peptide (C4BP), was chosen from six candidate-peptides based on their ability to bind to frozen sections of triple-negative breast cancer, 4T1 tumor ex vivo. The HA- C4BP conjugate showed a significant increase in tumor accumulation in 4T1-bearing mice after intravenous administration compared to unmodified HA. We further demonstrated that the systemic administration of bromelain conjugated C4BP-HA (C4BP-HA-Bro) potentiates the anti-tumor efficacy of liposomal doxorubicin. C4BP-HA-Bro decreased the number and length of collagen fibers and improved the distribution of doxorubicin within the tumor. No infusion reaction was noted after delivery of C4BP-HA-Bro. C4BP-HA thus offers a potential for effective and safe delivery of bromelain for improved intratumoral delivery of therapeutics.

Investigating multidimensional characteristics of noise signals with tones from building mechanical systems and their effects on annoyance.

This paper investigates multidimensional characteristics of tonal noise from heating, ventilation, and air-conditioning systems, besides loudness and tonality, to improve prediction of annoyance. Two studies were conducted: multidimensional scaling (MDS) analysis to determine what other perceptual signal characteristics are important and perceptual weight analysis (PWA) to understand the impact of multiple tones in a signal. In the MDS study, paired comparison tasks were conducted to gather similarity and annoyance data. Results show that the latent perceptual dimensions are related to the signal's tonality, loudness, sharpness, and roughness. Including metrics for these perceptions, except roughness, improves the performance of earlier annoyance prediction models. Including both sharpness and tonal audibility does not further improve prediction performance, though. In the PWA study, noise stimuli with five-tone complexes between 125 Hz and 2 kHz were generated for subjective testing to obtain a perceptual weighting function. The levels of each tone were randomly adjusted for every trial, and both harmonic and inharmonic tone complexes were utilized. The PWA result was applied as a spectral weighting function to calculate a proposed weighted-sum tonal audibility metric. Utilizing the proposed metric instead of the traditional tonal audibility metric improves annoyance prediction to a similar degree as including sharpness.

Listening Effort by Native and Nonnative Listeners Due to Noise, Reverberation, and Talker Foreign Accent During English Speech Perception.

Purpose Understanding speech in complex realistic acoustic environments requires effort. In everyday listening situations, speech quality is often degraded due to adverse acoustics, such as excessive background noise level (BNL) and reverberation time (RT), or talker characteristics such as foreign accent ( Mattys, Davis, Bradlow, & Scott, 2012 ). In addition to factors affecting the quality of the input acoustic signals, listeners' individual characteristics such as language abilities can also make it more difficult and effortful to understand speech. Based on the Framework for Understanding Effortful Listening ( Pichora-Fuller et al., 2016 ), factors such as adverse acoustics, talker accent, and listener language abilities can all contribute to increasing listening effort. In this study, using both a dual-task paradigm and a self-report questionnaire, we seek to understand listening effort in a wide range of realistic classroom acoustic conditions as well as varying talker accent and listener English proficiency. Method One hundred fifteen native and nonnative adult listeners with normal hearing were tested in a dual task of speech comprehension and adaptive pursuit rotor (APR) under 15 acoustic conditions from combinations of BNLs and RTs. Listeners provided responses on the NASA Task Load Index (TLX) questionnaire immediately after completing the dual task under each acoustic condition. The NASA TLX surveyed 6 dimensions of perceived listening effort: mental demand, physical demand, temporal demand, effort, frustration, and perceived performance. Fifty-six listeners were tested with speech produced by native American English talkers; the other 59 listeners, with speech from native Mandarin Chinese talkers. Based on their 1st language learned during childhood, 3 groups of listeners were recruited: listeners who were native English speakers, native Mandarin Chinese speakers, and native speakers of other languages (e.g., Hindu, Korean, and Portuguese). Results Listening effort was measured objectively through the APR task performance and subjectively using the NASA TLX questionnaire. Performance on the APR task did not vary with changing acoustic conditions, but it did suggest increased listening effort for native listeners of other languages compared to the 2 other listener groups. From the NASA TLX, listeners reported feeling more frustrated and less successful in understanding Chinese-accented speech. Nonnative listeners reported more listening effort (i.e., physical demand, temporal demand, and effort) than native listeners in speech comprehension under adverse acoustics. When listeners' English proficiency was controlled, higher BNL was strongly related to a decrease in perceived performance, whereas such relationship with RT was much weaker. Nonnative listeners who shared the foreign talkers' accent reported no change in listening effort, whereas other listeners reported more difficulty in understanding the accented speech. Conclusions Adverse acoustics required more effortful listening as measured subjectively with a self-report NASA TLX. This subjective scale was more sensitive than a dual task that involved speech comprehension, which was beyond sentence recall. It was better at capturing the negative impacts on listening effort from acoustic factors (i.e., both BNL and RT), talker accent, and listener language abilities.

Treatment outcomes of locally advanced cervical cancer by histopathological types in a single institution: A propensity score matching study.

BACKGROUND: In the current National Comprehensive Cancer Network (NCCN) guidelines, the standard treatment methods revealed no difference between locally advanced cervical (LAC) adenocarcinoma/adenosquamous carcinoma (AC/ASC) and LAC squamous cell carcinoma (SCC). The aim of this study was to compare the treatment outcomes of LAC AC/ASC with LAC SCC through the propensity score matching (PSM) analysis. METHODS: This retrospective study enrolled 181 LAC cancer patients who were treated with intensity modulated radiotherapy/volumetric modulated arc therapy and concurrent weekly cisplatin 30-40 mg/m2. In total, there were 151 LAC SCC patients and 30 LAC AC/ASC patients. The endpoints were overall survival (OS), disease-free survival (DFS), locoregional failure-free survival (LRFFS), and distant metastasis-free survival (DMFS). A 1:1 ratio PSM analysis was performed using the nearest neighbor method with a caliper of 0.20. Treatment outcomes were compared between 30 matched LAC SCC patients and 30 LAC AC/ASC patients. RESULTS: Before a 1:1 ratio PSM, the 5-year OS, DFS, LRFFS, and DMFS in the LAC SCC group were 78.6%, 71.3%, 88.2%, and 76.2%, respectively. After a 1:1 ratio PSM, the 5-year OS, DFS, LRFFS, and DMFS in the LAC AC/ASC group were 46.0%, 43.3%, 70.0%, and 45.4%, respectively, which were all significantly inferior than the rates of 90.0%, 75.8%, 96.6%, and 78.8% in the matched LAC SCC group, respectively (p < 0.05). CONCLUSION: LAC AC/ASC carries a poorer prognosis than LAC SCC. LAC AC/ASC needs more aggressive treatment in order to achieve higher OS and DFS.

Effects of noise, reverberation and foreign accent on native and non-native listeners' performance of English speech comprehension.

A large number of non-native English speakers may be found in American classrooms, both as listeners and talkers. Little is known about how this population comprehends speech in realistic adverse acoustical conditions. A study was conducted to investigate the effects of background noise level (BNL), reverberation time (RT), and talker foreign accent on native and non-native listeners' speech comprehension, while controlling for English language abilities. A total of 115 adult listeners completed comprehension tasks under 15 acoustic conditions: three BNLs (RC-30, RC-40, and RC-50) and five RTs (from 0.4 to 1.2 s). Fifty-six listeners were tested with speech from native English-speaking talkers and 59 with native Mandarin-Chinese-speaking talkers. Results show that, while higher BNLs were generally more detrimental to listeners with lower English proficiency, all listeners experienced significant comprehension deficits above RC-40 with native English talkers. This limit was lower (i.e., above RC-30), however, with Chinese talkers. For reverberation, non-native listeners as a group performed best with RT up to 0.6 s, while native listeners performed equally well up to 1.2 s. A matched foreign accent benefit has also been identified, where the negative impact of higher reverberation does not exist for non-native listeners who share the talker's native language.

Comparative short-term safety of bolus versus maintenance iron dosing in hemodialysis patients: a replication study.

BACKGROUND: Recent research has reported that patients receiving bolus (frequent large doses to achieve iron repletion) versus maintenance dosing of iron have an increased short-term risk of infection, but a similar risk of cardiovascular events. We sought to determine whether these findings could be replicated using the same methods and a different data source. METHODS: Clinical data from 6,605 patients of a small U.S. dialysis provider merged with Medicare claims data were examined. Iron dosing patterns (bolus, maintenance, no iron) were identified during 1-month exposure periods and cardiovascular and infection-related outcomes were assessed during 3-month follow-up periods. The effects of bolus versus maintenance dosing were assessed using Cox proportional hazards regression analyses to estimate hazard ratios and semiparametric additive risk models to estimate hazard rate differences, controlling for demographic and clinical characteristics, laboratory values and medications, and comorbidities. RESULTS: 48,050 exposure/follow-up periods were examined. 13.9 percent of the exposure periods were bolus dosing, 49.3 percent were maintenance dosing, and the remainder were no iron use. All of the adjusted hazard ratios were >1.00 for the infection-related outcomes, suggesting that bolus dosing increases the risk of these events. The effects were greatest for hospitalized for infection of any major organ system (hazard ratio 1.13 (1.03, 1.24)) and use of intravenous antibiotics (hazard ratio 1.08 (1.02, 1.15). When examining the subgroup of individuals with catheters, the hazard ratios for the infection-related outcomes were generally greater than in the overall sample. There was little association between type of dosing practice and cardiovascular outcomes. CONCLUSIONS: Results of this study provide further evidence of the association between bolus dosing and increased infection risk, particularly in the subgroup of patients with a catheter, and of the lack of an association between dosing practices and cardiovascular outcomes.

Melatonin in children with autism spectrum disorders: endogenous and pharmacokinetic profiles in relation to sleep.

Supplemental melatonin has been used to treat sleep onset insomnia in children with autism spectrum disorders (ASD), although the mechanism of action is uncertain. We assessed endogenous and supplemental melatonin profiles in relation to sleep in nine children with ASD. In endogenous samples, maximal melatonin concentration (C(max)) and time to peak concentration (T(max)) were comparable to those previously published in the literature for typically developing children, and dim light melatonin onsets were captured in the majority of children. In treatment samples (supplemental melatonin), melatonin parameters were also comparable to those previously published for typically developing children. Our findings support that children with ASD and insomnia responsive to low dose melatonin treatment have relatively normal profiles of endogenous and supplemental melatonin.

Improvement in social deficits in autism spectrum disorders using a theatre-based, peer-mediated intervention.

Social Emotional NeuroScience Endocrinology Theatre is a novel intervention program aimed at improving reciprocal social interaction in youth with autism spectrum disorder (ASD) using behavioral strategies and theatrical techniques in a peer-mediated model. Previous research using a 3-month model showed improvement in face perception, social interaction, and reductions in stress. The current study assessed a 2-week summer camp model. Typically developing peers were trained and paired with ASD youth (8-17 years). Social perception and interaction skills were measured before and after treatment using neuropsychological and parental measures. Behavioral coding by reliable, independent raters was conducted within the treatment context (theatre) and outside the setting (playground). Salivary cortisol levels to assess physiological arousal were measured across contexts (home, theatre, and playground). A pretest-posttest design for within-group comparisons was used, and prespecified pairwise comparisons were achieved using a nonparametric Wilcoxon signed-rank test. Significant differences were observed in face processing, social awareness, and social cognition (P < 0.05). Duration of interaction with familiar peers increased significantly over the course of treatment (P < 0.05), while engagement with novel peers outside the treatment setting remained stable. Cortisol levels rose on the first day of camp compared with home values yet declined by the end of treatment and further reduced during posttreatment play with peers. Results corroborate previous findings that the peer-mediated theatre program contributes to improvement in core social deficits in ASD using a short-term, summer camp treatment model. Future studies will explore treatment length and peer familiarity to optimize and generalize gains.

Intravenous iron supplementation practices and short-term risk of cardiovascular events in hemodialysis patients.

BACKGROUND & OBJECTIVES: Intravenous iron supplementation is widespread in the hemodialysis population, but there is uncertainty about the safest dosing strategy. We compared the safety of different intravenous iron dosing practices on the risk of adverse cardiovascular outcomes in a large population of hemodialysis patients. DESIGN SETTINGS PARTICIPANTS & MEASUREMENTS: A retrospective cohort was created from the clinical database of a large dialysis provider (years 2004-2008) merged with administrative data from the United States Renal Data System. Dosing comparisons were (1) bolus (consecutive doses ≥ 100 mg exceeding 600 mg during one month) versus maintenance (all other iron doses during the month); and (2) high (> 200 mg over 1 month) versus low dose (≤ 200 mg over 1 month). We established a 6-month baseline period (to identify potential confounders and effect modifiers), a one-month iron exposure period, and a three-month follow-up period. Outcomes were myocardial infarction, stroke, and death from cardiovascular disease. RESULTS: 117,050 patients contributed 776,203 unique iron exposure/follow-up periods. After adjustment, we found no significant associations of bolus dose versus maintenance, hazards ratio for composite outcome, 1.03 (95% C.I. 0.99, 1.07), or high dose versus low dose intravenous iron, hazards ratio for composite outcome, 0.99 (95% C.I. 0.96, 1.03). There were no consistent associations of either high or bolus dose versus low or maintenance respectively among pre-specified subgroups. CONCLUSIONS: Strategies favoring large doses of intravenous iron were not associated with increased short-term cardiovascular morbidity and mortality. Investigation of the long-term safety of the various intravenous iron supplementation strategies may still be warranted.

Infection risk with bolus versus maintenance iron supplementation in hemodialysis patients.

Intravenous iron may promote bacterial growth and impair host defense, but the risk of infection associated with iron supplementation is not well defined. We conducted a retrospective cohort study of hemodialysis patients to compare the safety of bolus dosing, which provides a large amount of iron over a short period of time on an as-needed basis, with maintenance dosing, which provides smaller amounts of iron on a regular schedule to maintain iron repletion. Using clinical data from 117,050 patients of a large US dialysis provider merged with data from Medicare's ESRD program, we estimated the effects of iron dosing patterns during repeated 1-month exposure periods on risks of mortality and infection-related hospitalizations during the subsequent 3 months. Of 776,203 exposure/follow-up pairs, 13% involved bolus dosing, 49% involved maintenance dosing, and 38% did not include exposure to iron. Multivariable additive risk models found that patients receiving bolus versus maintenance iron were at increased risk of infection-related hospitalization (risk difference [RD], 25 additional events/1000 patient-years; 95% confidence interval [CI], 16 to 33) during follow-up. Risks were largest among patients with a catheter (RD, 73 events/1000 patient-years; 95% CI, 48 to 99) and a recent infection (RD, 57 events/1000 patient-years; 95% CI, 19 to 99). We also observed an association between bolus dosing and infection-related mortality. Compared with no iron, maintenance dosing did not associate with increased risks for adverse outcomes. These results suggest that maintenance iron supplementation may result in fewer infections than bolus dosing, particularly among patients with a catheter.

The comparative short-term effectiveness of iron dosing and formulations in US hemodialysis patients.

BACKGROUND: Intravenous iron is used widely in hemodialysis, yet there are limited data on the effectiveness of contemporary dosing strategies or formulation type. METHODS: We conducted a retrospective cohort study using data from the clinical database of a large dialysis provider (years 2004-2008) merged with administrative data from the US Renal Data System to compare the effects of intravenous iron use on anemia management. Dosing comparisons were bolus (consecutive doses ≥100 mg exceeding 600 mg during 1 month) versus maintenance (all other iron doses during the month); and high (>200 mg over 1 month) versus low dose (≤200 mg over 1 month). Formulation comparison was administration of ferric gluconate versus iron sucrose over 1 month. Outcomes were hemoglobin, epoetin dose, transferrin saturation, and serum ferritin during 6 weeks of follow-up. RESULTS: We identified 117,050 patients for the dosing comparison, and 66,207 patients for the formulation comparison. Bolus dosing was associated with higher average adjusted hemoglobin (+0.23 g/dL; 95% confidence interval [CI], 0.21-0.26), transferrin saturation (+3.31%; 95% CI, 2.99-3.63), serum ferritin (+151 µg/L; 95% CI, 134.9-168.7), and lower average epoetin dose (-464 units; 95% CI, -583 to -343) compared with maintenance. Similar trends were observed with high-dose iron versus low-dose. Iron sucrose was associated with higher adjusted average hemoglobin (+0.16 g/dL; 95% CI, 0.12-0.19) versus ferric gluconate. CONCLUSIONS: Strategies favoring large doses of intravenous iron or iron sucrose lead to improved measures of anemia management. These potential benefits should be weighed against risks, which currently remain incompletely characterized.

Melatonin for sleep in children with autism: a controlled trial examining dose, tolerability, and outcomes.

Supplemental melatonin has shown promise in treating sleep onset insomnia in children with autism spectrum disorders (ASD). Twenty-four children, free of psychotropic medications, completed an open-label dose-escalation study to assess dose-response, tolerability, safety, feasibility of collecting actigraphy data, and ability of outcome measures to detect change during a 14-week intervention. Supplemental melatonin improved sleep latency, as measured by actigraphy, in most children at 1 or 3 mg dosages. It was effective in week 1 of treatment, maintained effects over several months, was well tolerated and safe, and showed improvement in sleep, behavior, and parenting stress. Our findings contribute to the growing literature on supplemental melatonin for insomnia in ASD and inform planning for a large randomized trial in this population.

Definitive intensity-modulated radiation therapy with concurrent chemotherapy for patients with locally advanced cervical cancer.

OBJECTIVE: Cervical cancer is one of the most common cancers diagnosed in women worldwide. Concurrent chemoradiotherapy (CCRT) is the mainstay treatment for locally advanced cervical cancer. The purpose of this study was to investigate the treatment outcomes and toxicity of definitive intensity-modulated radiotherapy (IMRT) with concurrent chemotherapy for patients with locally advanced carcinoma of the cervix in a single institution. METHODS: Between January 2004 and November 2008, 109 patients with stage IB2-IVA cervical carcinoma treated with IMRT and concurrent cisplatin-based chemotherapy were evaluated retrospectively. All patients received external irradiation of 45-54 Gy with an IMRT technique. High dose rate brachytherapy of 20-33.5 Gy was prescribed to point A as a local boost. Each patient received concurrent cisplatin-based chemotherapy monthly or weekly. The endpoints were overall survival (OS), local failure-free survival (LFFS) and disease-free survival (DFS). Patients were assessed for acute toxicity weekly according to the Common Toxicity Criteria for Adverse Events (CTCAE), version 3.0. Late toxicity was evaluated according to RTOG-EORTC Late Radiation Morbidity Scoring Schema. RESULTS: The median follow up time for all surviving patients was 32.5 months, with a range from 5 to 75 months. The 3-year OS, LFFS and DFS were 78.2%, 78.1% and 67.6%, respectively. Three (2.7%) patients developed grade 3 or greater acute gastrointestinal (GI) toxicity and 26 (23.9%) patients developed grade 3 or greater hematological toxicity. Five (4.6%) patients developed grade 3 or greater chronic GI toxicity and 7 (6.4%) patients developed grade 3 or greater genitourinary system toxicity. CONCLUSIONS: Good outcomes were achieved with definitive IMRT and concurrent chemotherapy for patients with locally advanced cervical cancer and the combined treatment was well tolerated with favorable acute and late toxicity.

Relation of melatonin to sleep architecture in children with autism.

Children with autism often suffer from sleep disturbances, and compared to age-matched controls, have decreased melatonin levels, as indicated by urine levels of the primary melatonin metabolite, 6-sulfatoxymelatonin (6-SM). We therefore investigated the relationship between 6-SM levels and sleep architecture in children with autism spectrum disorders (ASD). Twenty-three children, aged 4-10 years, completed two nights of polysomnography and one overnight urine collection for measurement of urinary 6-SM excretion rate. Parents completed the Children's Sleep Habits Questionnaire. We found that higher urinary 6-SM excretion rates were associated with increased N3 sleep, decreased N2 sleep, and decreased daytime sleepiness. The results warrant further examination to examine the effects of supplemental melatonin on sleep architecture and daytime sleepiness.