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Seasonal influenza epidemics result in high levels of healthcare utilization. Vaccination is an effective strategy to reduce the influenza-related burden of disease. However, reporting vaccine effectiveness does not convey the population impacts of influenza vaccination. We aimed to calculate the burden of influenza-related hospitalizations and emergency department (ED) attendance averted by influenza vaccination in Victoria, Australia, from 2017 to 2019, and associated economic savings. We applied a compartmental model to hospitalizations and ED attendances with influenza-specific, and pneumonia and influenza (P&I) with the International Classification of Diseases, 10th Revision, Australian Modification (ICD-10-AM) diagnostic codes of J09-J11 and J09-J18, respectively. We estimated an annual average of 7657 (120 per 100000 population) hospitalizations and 20560 (322 per 100000 population) ED attendances over the study period, associated with A$85 million hospital expenditure. We estimated that influenza vaccination averted an annual average of 1182 [range: 556 - 2277] hospitalizations and 3286 [range: 1554 - 6257] ED attendances and reduced the demand for healthcare services at the influenza season peak. This equated to approximately A13 [range: A6 - A25] million of savings over the study period. Calculating the burden averted is feasible in Australia and auseful approach to demonstrate the health and economic benefits of influenza vaccination.

BACKGROUND/OBJECTIVES: School meals are an important source of nutrition for children and have been found to help mitigate food insecurity. This study evaluated the association between food insecurity and school meal participation and whether parental perceptions about school meals differ by food security status. METHODS: In May 2022, 1110 Californian parents of K-12 students shared their perceptions about school meals, including meal quality, healthiness, stigma, and benefits, as well as their childs participation in school meals, in an online survey. Household food security was determined using the USDA 6-item module. Logistic and Poisson regression models were used for analysis. RESULTS: The prevalence of household food insecurity was 56.2% (69.6% in households of students eligible for free meals, 55.9% in reduced-price, and 38.3% in non-eligible). Many of the reported benefits of school meals (saving families money and time) were equally highly endorsed by parents with and without food insecurity (p > 0.05). Parents reporting food insecurity had less favorable perceptions of school meals and perceived more stigma (p < 0.05). Food insecurity was positively associated with breakfast participation, especially among elementary school students and students not eligible for free or reduced-price meals (FRPMs) (p < 0.05). CONCLUSIONS: Food insecurity is prevalent among California families with school-age children, even in families not eligible for federal FRPMs. Food-insecure households have more negative perceptions of school meals and experience more stigma, though they also report higher breakfast participation. Improving school meal quality and appeal, ensuring parents are familiar with meal quality and healthfulness, and reducing stigma may ease food insecurity while improving childrens health.

INTRODUCTION: Personalized and tumor-informed circulating tumor DNA (ctDNA) testing is feasible and allows for molecular residual disease (MRD) identification in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: In this retrospective analysis of commercial cases from multiple US institutions, personalized, tumor-informed, whole-exome sequenced, and germline-controlled ctDNA levels were quantified and analyzed in patients with PDAC. Plasma samples (n = 1329) from 298 clinically validated patients were collected at diagnosis, perioperatively (MRD-window; within 2-12 weeks after surgery, before therapy), and during surveillance (>12 weeks post-surgery if no ACT or starting 4 weeks post-ACT) from November 2019 to March 2023. RESULTS: Of the initially diagnosed patients with stages I-III PDAC who went for resection, the median follow-up time from surgery was 13 months (range 0.1-214). Positive ctDNA detection rates were 29% (29/100) and 29.6% (45/152) during the MRD and surveillance windows, respectively. Positive ctDNA detection was significantly associated with shorter DFS within the MRD window (median DFS of 6.37 months for ctDNA-positive vs 33.31 months for ctDNA-negative patients; HR: 5.45, P

Research on action-based timing has shed light on the temporal dynamics of sensorimotor coordination. This study investigates the neural mechanisms underlying action-based timing, particularly during finger-tapping tasks involving synchronized and syncopated patterns. Twelve healthy participants completed a continuation task, alternating between tapping in time with an auditory metronome (pacing) and continuing without it (continuation). Electroencephalography data were collected to explore how neural activity changes across these coordination modes and phases. We applied deep learning methods to classify single-trial electroencephalography data and predict behavioral timing conditions. Results showed significant classification accuracy for distinguishing between pacing and continuation phases, particularly during the presence of auditory cues, emphasizing the role of auditory input in motor timing. However, when auditory components were removed from the electroencephalography data, the differentiation between phases became inconclusive. Mean accuracy asynchrony, a measure of timing error, emerged as a superior predictor of performance variability compared to inter-response interval. These findings highlight the importance of auditory cues in modulating motor timing behaviors and present the challenges of isolating motor activation in the absence of auditory stimuli. Our study offers new insights into the neural dynamics of motor timing and demonstrates the utility of deep learning in analyzing single-trial electroencephalography data.

Punishment serves as a balancing force that dissuades people from acting selfishly, which complements cooperation as an essential characteristic for the prosperity of human societies. Past studies using economic games with two options (cooperation and defection) reported that cooperation decisions are generally faster than defection decisions and that time pressure possibly induces human players to be more intuitive and thus cooperative. However, it is unclear where punishment decisions sit on this time spectrum. Therefore, we recruited human players and implemented two series of online network games with cooperation, defection, and punishment options. First, we find that punishment decisions are slower than cooperation or defection decisions across both game series. Second, we find that imposing experimental time pressure on in-game decisions neither reduces nor increases the frequency of punishment decisions, suggesting that time pressure may not directly interact with the mechanisms that drive players to choose to punish.

BACKGROUND: Olezarsen is a GalNAc3-conjugated, hepatic-targeted antisense oligonucleotide that lowers apolipoprotein C-III (apoC-III) and triglyceride levels. The efficacy and safety of olezarsen has not previously been studied in ethnically diverse American populations. The aim of this study is to assess the effect of olezarsen in healthy Japanese Americans. METHODS: A randomized, placebo-controlled, double-blind phase 1 study was performed in 28 healthy Japanese American participants treated with olezarsen in single-ascending doses (SAD; 30, 60, 90 mg) or multiple doses (MD; 60 mg every 4 weeks for 4 doses). The primary, secondary, and exploratory objectives were safety and tolerability, pharmacokinetics, and effects of olezarsen on fasting serum triglycerides and apoC-III, respectively. RESULTS: There were 20 participants (16 active:4 placebo) in the SAD part of the study, and 8 participants (6 active:2 placebo) in the MD part of the study. For the primary endpoint, no serious adverse events or clinically relevant laboratory abnormalities were reported. The majority of olezarsen plasma exposure occurred within 24 h post-dose. In the SAD cohorts at Day 15 the percentage reduction in apoC-III/TG was - 39.4%/ - 17.8%, - 60.8%/ - 52.7%, and - 68.1%/ - 39.2% in the 30, 60 and 90 mg doses, respectively, vs 2.3%/44.5% increases in placebo. In the MD cohort, at Day 92 the percentage reduction in apoC-III/TG was - 81.6/ - 73.8% vs - 17.2/ - 40.8% reduction in placebo. Favorable changes were also present in VLDL-C, apoB and HDL-C. CONCLUSIONS: Single- and multiple-dose administration of olezarsen was safe, was well tolerated, and significantly reduced apoC-III and triglyceride levels in healthy Japanese Americans.

The Brazilian Amazon is a vast area with limited health care resources. To assess the epidemiology of critically ill acute kidney injury (AKI) patients in this area, a prospective cohort study of 1029 adult patients of the three intensive care units (ICUs) of Rio Branco city, the capital of Acre state, were evaluated from February 2014 to February 2016. The incidence of AKI was 53.3%. Risk factors for AKI included higher age, nonsurgical patients, admission to the ICU from the ward, higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores at ICU admission, and positive fluid balance > 1500 ml/24 hours in the days before AKI development in the ICU, with aOR of 1.3 (95% CI 1.03-1.23), 1.47 (95% CI 1.07-2.03), 1.96 (95% CI 1.40-2.74), 1.05 (95% CI 1.03-1.08) for each unit increase, and 1.62 (95% CI 1.16-2.26), respectively. AKI was associated with higher ICU mortality (aOR 2.03, 95% CI 1.29-3.18). AKI mortality was independently associated with higher age, nonsurgical patients, sepsis at ICU admission, presence of shock or use of vasoactive drugs, mechanical ventilation and mean positive fluid balance in the ICU > 1500 ml/24 hours, both during ICU follow-up, with aOR 1.27 (95% CI 1.14-1.43) for each 10-year increase, 1.64 (95% CI 1.07-2.52), 2.35 (95% CI 1.14-4.83), 1.88 (95% CI 1.03-3.44), 6.73 (95% CI 4.08-11.09), 2.31 (95% CI 1.52-3.53), respectively. Adjusted hazard ratios for AKI mortality 30 and 31-180 days after ICU discharge were 3.13 (95% CI 1.84-5.31) and 1.69 (95% CI 0.99-2.90), respectively. AKI incidence was strikingly high among critically ill patients in the Brazilian Amazon. The AKI etiology, risk factors and outcomes were similar to those described in high-income countries, but mortality rates were higher.

BACKGROUND: Video games have rapidly become mainstream in recent decades, with over half of the US population involved in some form of digital gaming. However, concerns regarding the potential harms of excessive, disordered gaming have also risen. Internet gaming disorder (IGD) has been proposed as a tentative psychiatric disorder that requires further study by the American Psychological Association (APA) and is recognized as a behavioral addiction by the World Health Organization. Substance use among gamers has also become a concern, with caffeinated or energy drinks and prescription stimulants commonly used for performance enhancement. OBJECTIVE: This study aimed to identify substance use patterns and health-related concerns among gamers among a population of Reddit users. METHODS: We used the public streaming Reddit application programming interface to collect and analyze all posts from the popular subreddit, r/StopGaming. From this corpus of posts, we filtered the dataset for keywords associated with common substances that may be used to enhance gaming performance. We then applied an inductive coding approach to characterize substance use behaviors, gaming genres, and physical and mental health concerns. Potential disordered gaming behavior was also identified using the tentative IGD guidelines proposed by the APA. A chi-square test of independence was used to assess the association between gaming disorder and substance use characteristics, and multivariable logistic regression was used to analyze whether mental health discussion or the mention of any substance with sufficient sample size was significantly associated with IGD. RESULTS: In total, 10,551 posts were collected from Reddit from June 2017 to December 2022. After filtering the dataset for substance-related keywords, 1057 were included for further analysis, of which 286 mentioned both gaming and the use of ≥1 substances. Among the 286 posts that discussed both gaming and substance use, the most mentioned substances were alcohol (n=132), cannabis (n=104), and nicotine (n=48), while the most mentioned genres were role-playing games (n=120), shooters (n=90), and multiplayer online battle arenas (n=43). Self-reported behavior that aligned with the tentative guidelines for IGD was identified in 66.8% (191/286) posts. More than half, 62.9% (180/286) of the posts, discussed a health issue, with the majority (n=144) cited mental health concerns. Common mental health concerns discussed were depression and anxiety. There was a significant association between IGD and substance use (P

Women living with HIV/AIDS (WLHA) encounter numerous challenges, such as stigma and gender disparities, that hinder their access to care, especially in patriarchal societies like Vietnam. We developed a hybrid intervention with online and offline (in-person) components to empower WLHA in Vietnam. The intervention was pilot tested with 91 WLHA in Hanoi. During baseline and 4-month, study investigators delivered two in-person sessions, one Zoom session, and 15 weeks of Zalo (social media platform) discussions to enhance positive coping strategies, treatment utilization and adherence, and engagement of support from family and peers. The participants continued their Zalo discussions from 4-month to 6-month without investigators' involvement. Intervention outcomes, including active coping and perceived barriers to care, were evaluated at baseline, 4-, and 6-month surveys. Mixed-effects regression models showed that the participants' active coping significantly increased from baseline (50.5 ± 9.4) to 4-month (53.8 ± 6.2; p = 0.0001), although there was a slight decrease at 6-month (52.8 ± 7.2), the change from 4-month to 6-month was not significantly significant (p = 0.3256). There was a significant reduction in participants' perceived barriers to care, from 19.8 ± 5.2 at baseline to 17.4 ± 5.2 at 4-month (p

PurposeWe aimed to estimate health state utility values (HSUVs) for the key health states found in opioid use disorder (OUD) cost-effectiveness models in the published literature.MethodsData obtained from six trials representing 1,777 individuals with OUD. We implemented mapping algorithms to harmonize data from different measures of quality of life (the SF-12 Versions 1 and 2 and the EQ-5D-3 L). We performed a regression analysis to quantify the relationship between HSUVs and the following variables: days of extra-medical opioid use in the past 30 days, injecting behaviors, treatment with medications for OUD, HIV status, and age. A secondary analysis explored the impact of opioid withdrawal symptoms.ResultsThere were statistically significant reductions in HSUVs associated with extra-medical opioid use (-0.002 (95% CI [-0.003,-0.0001]) to -0.003 (95% CI [-0.005,-0.002]) per additional day of heroin or other opiate use, respectively), drug injecting compared to not injecting (-0.043 (95% CI [-0.079,-0.006])), HIV-positive diagnosis compared to no diagnosis (-0.074 (95% CI [-0.143,-0.005])), and age (-0.001 per year (95% CI [-0.003,-0.0002])). Parameters associated with medications for OUD treatment were not statistically significant after controlling for extra-medical opioid use (0.0131 (95% CI [-0.0479,0.0769])), in line with prior studies. The secondary analysis revealed that withdrawal symptoms are a fundamental driver of HSUVs, with predictions of 0.817 (95% CI [0.768, 0.858]), 0.705 (95% CI [0.607, 0.786]), and 0.367 (95% CI [0.180, 0.575]) for moderate, severe, and worst level of symptoms, respectively.ConclusionWe observed HSUVs for OUD that were higher than those from previous studies that had been conducted without input from people living with the condition.

BACKGROUND AND OBJECTIVE: Upadacitinib is indicated for diseases affecting persons of childbearing potential including rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, atopic dermatitis, Crohns disease, and ulcerative colitis; however, teratogenicity was observed in animal studies. Given the potential for human fetal risk, pregnancy avoidance measures were required during clinical trials. This analysis describes pregnancy outcomes in patients exposed to upadacitinib during pregnancy. METHODS: Clinical trial and postmarketing cases of in utero exposure to upadacitinib were identified in AbbVies safety database through 25 April, 2023. Analysis of clinical trial cases and postmarketing reports are presented separately; prospective and retrospectively reported pregnancy outcomes are integrated for each. Descriptive rates are presented to summarize outcomes. RESULTS: There were 128 maternal upadacitinib-exposed pregnancies with known outcomes identified; 80 and 48 pregnancies were reported in clinical trials and the postmarketing setting, respectively. In clinical trials (mean in utero exposure of 5 weeks, 3 days), live births (54%), spontaneous abortions (24%), elective terminations (21%), and ectopic pregnancy (1%) were reported. There was one report of a congenital malformation: a 35-week infant with an atrial septal defect. In postmarketing cases, live births (46%), spontaneous abortions (38%), elective terminations (15%), and ectopic pregnancy (2%) were reported. CONCLUSIONS: As the data are limited for in utero exposure to upadacitinib, definitive conclusions cannot be drawn regarding the effect of upadacitinib on pregnancy outcomes. Rates of adverse pregnancy outcomes with upadacitinib exposure were comparable to rates observed in the general population or patients with autoimmune inflammatory diseases. To date, no apparent evidence of teratogenicity exists in the analyses of human pregnancies exposed to upadacitinib during the first trimester.

Outbreaks of monkeypox (mpox) have historically resulted from zoonotic spillover of clade I monkeypox virus (MPXV) in Central Africa and clade II MPXV in West Africa. In 2022, subclade IIb caused a global epidemic linked to transmission through sexual contact. Here we describe the epidemiological and genomic features of an mpox outbreak in a mining region in eastern Democratic Republic of the Congo, caused by clade I MPXV. Surveillance data collected between September 2023 and January 2024 identified 241 suspected cases. Genomic analysis demonstrates a distinct clade I lineage divergent from previously circulating strains in the Democratic Republic of the Congo. Of the 108 polymerase chain reaction-confirmed mpox cases, the median age of individuals was 22 years, 51.9% were female and 29% were sex workers, suggesting a potential role for sexual transmission. The predominance of APOBEC3-type mutations and the estimated emergence time around mid-September 2023 imply recent sustained human-to-human transmission.

Most studies about the menstrual cycle are laboratory-based, in small samples, with infrequent sampling, and limited to young individuals. Here, we use wearable and diary-based data to investigate menstrual phase and age effects on finger temperature, sleep, heart rate (HR), physical activity, physical symptoms, and mood. A total of 116 healthy females, without menstrual disorders, were enrolled: 67 young (18-35 years, reproductive stage) and 53 midlife (42-55 years, late reproductive to menopause transition). Over one menstrual cycle, participants wore Oura ring Gen2 to detect finger temperature, HR, heart rate variability (root mean square of successive differences between normal heartbeats [RMSSD]), steps, and sleep. They used luteinizing hormone (LH) kits and daily rated sleep, mood, and physical symptoms. A cosinor rhythm analysis was applied to detect menstrual oscillations in temperature. The effect of menstrual cycle phase and group on all other variables was assessed using hierarchical linear models. Finger temperature followed an oscillatory trend indicative of ovulatory cycles in 96 participants. In the midlife group, the temperature rhythms mesor was higher, but period, amplitude, and number of days between menses and acrophase were similar in both groups. In those with oscillatory temperatures, HR was lowest during menses in both groups. In the young group only, RMSSD was lower in the late-luteal phase than during menses. Overall, RMSSD was lower, and number of daily steps was higher, in the midlife group. No significant menstrual cycle changes were detected in wearable-derived or self-reported measures of sleep efficiency, duration, wake-after-sleep onset, sleep onset latency, or sleep quality. Mood positivity was higher around ovulation, and physical symptoms manifested during menses. Temperature and HR changed across the menstrual cycle; however, sleep measures remained stable in these healthy young and midlife individuals. Further work should investigate over longer periods whether individual- or cluster-specific sleep changes exist, and if a buffering mechanism protects sleep from physiological changes across the menstrual cycle.

Brain aging process is influenced by various lifestyle, environmental and genetic factors, as well as by age-related and often coexisting pathologies. Magnetic resonance imaging and artificial intelligence methods have been instrumental in understanding neuroanatomical changes that occur during aging. Large, diverse population studies enable identifying comprehensive and representative brain change patterns resulting from distinct but overlapping pathological and biological factors, revealing intersections and heterogeneity in affected brain regions and clinical phenotypes. Herein, we leverage a state-of-the-art deep-representation learning method, Surreal-GAN, and present methodological advances and extensive experimental results elucidating brain aging heterogeneity in a cohort of 49,482 individuals from 11 studies. Five dominant patterns of brain atrophy were identified and quantified for each individual by respective measures, R-indices. Their associations with biomedical, lifestyle and genetic factors provide insights into the etiology of observed variances, suggesting their potential as brain endophenotypes for genetic and lifestyle risks. Furthermore, baseline R-indices predict disease progression and mortality, capturing early changes as supplementary prognostic markers. These R-indices establish a dimensional approach to measuring aging trajectories and related brain changes. They hold promise for precise diagnostics, especially at preclinical stages, facilitating personalized patient management and targeted clinical trial recruitment based on specific brain endophenotypic expression and prognosis.

In the United States, immigrant Latino men who have sex with men (ILMSM) are, compared to white MSM, disproportionately burdened by HIV and lack access to highly effective HIV prevention strategies, such as pre-exposure prophylaxis (PrEP). Qualitative research centered on exploring barriers that ILMSM experience in accessing PrEP and other sexual services is extremely limited, despite a high prevalence of HIV in this population. In this study, a purposive sample of ILMSM (n = 25) was recruited to participate in a semi-structured in-depth interview to identify the distinct barriers and facilitators ILMSM experience in accessing sexual health services given their complex intersectional identities of being an immigrant, Latino, and a sexual minority man. Using a thematic analysis approach, nine themes were generated from the data representing barriers and facilitators. Barriers included: (1) cost and a lack of health insurance, (2) complexity of PrEP assistance programs; (3) challenges related to the immigrant experience; (4) impact of gay stigma; and (5) communication challenges. Facilitators included: (1) improving affordability and accessibility of PrEP services; (2) receiving services from LGBT- or Latine LGBT-centered clinics; (3) receiving services from medical providers who are gay and/or Latino; and (4) providing targeted community outreach, education, and promotion of PrEP to ILMSM. While many of the barriers illuminated in the study were structural (e.g., cost and lack of health insurance), and not easy to overcome, the findings highlight a range of facilitators that can support access to PrEP and other sexual health services for ILMSM. Considering these findings, we suggest strategies that may enhance access to needed sexual health services among ILMSM.

BACKGROUND: The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. METHODS: Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. FINDINGS: Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. INTERPRETATION: Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. FUNDING: CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.

We linked 4 mpox cases in South Ubangi, Democratic Republic of the Congo, to transboundary transmission from Central African Republic. Viral genome sequencing demonstrated that the monkeypox virus sequences belonged to distinct clusters of subclade Ia. This finding demonstrates the borderless nature of mpox and highlights the need for vigilant regional surveillance.

INTRODUCTION: Staged treatment of high-energy periarticular tibia fractures involves temporization with closed reduction and external fixation, aiming to provide early reduction and stabilization while mitigating soft-tissue complications. Various external fixator configurations exist, including those that use a multipin clamp capable of holding multiple pins but limiting pin placement to a single plane. The purpose of this study was to compare clinical and radiographic outcomes and associated costs of standard and multipin outrigger clamp constructs in tibial plateau and pilon fractures treated with temporary external fixation. We hypothesized that use of the multipin clamp may be associated with poorly aligned reductions and increased complication rates. METHODS: A retrospective review of 100 patients with periarticular tibial plateau (AO/OTA: 41B/C) or pilon (43B/C) fracture at a Level 1 trauma center from 2014 to 2023 was conducted. Patient, injury, and complication characteristics were collected. Patients were categorized based on the external fixator clamp used: multipin (MP) or standard (S). Clinical outcomes and complication rates were assessed. Radiographic alignment was evaluated by the change in anterior and lateral distal tibial angles, and sagittal plane translation for pilon fractures, and medial and posterior proximal tibial angles for plateau fractures. RESULTS: 70 patients underwent standard (25 pilon, 45 plateau) and 30 multipin (10 pilon, 20 plateau) external fixation. MP and S groups showed no notable differences in demographics or injury characteristics. Both groups demonstrated comparable complication rates and radiological alignment outcomes, with no notable differences observed. MP constructs were more costly than standard systems. CONCLUSION: In this retrospective study of 100 patients, there was no difference in radiographic or clinical outcomes between the standard frame and multipin frame groups. Typical costs for the multipin frame constructs were $635 to $1249 more than the standard frame constructs.

BACKGROUND: Interindividual variability in oncology patients symptom experiences poses significant challenges in prioritizing symptoms for targeted intervention(s). In this study, computational approaches were used to unbiasedly characterize the heterogeneity of the symptom experience of oncology patients to elucidate symptom patterns and drivers of symptom burden. METHODS: Severity ratings for 32 symptoms on the Memorial Symptom Assessment Scale from 3088 oncology patients were analyzed. Gaussian Graphical Model symptom networks were constructed for the entire cohort and patient subgroups identified through unsupervised clustering of symptom co-severity patterns. Network characteristics were analyzed and compared using permutation-based statistical tests. Differences in demographic and clinical characteristics between subgroups were assessed using multinomial logistic regression. RESULTS: Network analysis of the entire cohort revealed three symptom clusters: constitutional, gastrointestinal-epithelial, and psychological. Lack of energy was identified as central to the network which suggests that it plays a pivotal role in patients overall symptom experience. Unsupervised clustering of patients based on shared symptom co-severity patterns identified six patient subgroups with distinct symptom patterns and demographic and clinical characteristics. The centrality of individual symptoms across the subgroup networks differed which suggests that different symptoms need to be prioritized for treatment within each subgroup. Age, treatment status, and performance status were the strongest determinants of subgroup membership. CONCLUSIONS: Computational approaches that combine unbiased stratification of patients and in-depth modeling of symptom relationships can capture the heterogeneity in patients symptom experiences. When validated, the core symptoms for each of the subgroups and the associated clinical determinants may inform precision-based symptom management.

Key HIV cure strategies involve reversing immune dysfunction and limiting the proliferation of infected T cells. We evaluate the safety of sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, in people with HIV (PWH) and study the impact of sirolimus on HIV-1 reservoir size and HIV-1-specific immunity in a single-arm study of 20 weeks of treatment in PWH on antiretroviral therapy (ART). Sirolimus treatment does not impact HIV-1-specific CD8 T cell responses but leads to a significant decrease in CD4+ T cell-associated HIV-1 DNA levels at 20 weeks of therapy in the primary efficacy population (n = 16; 31% decline, p = 0.008). This decline persists for at least 12 weeks following cessation of the study drug. Sirolimus treatment also leads to a significant reduction in CD4+ T cell cycling and PD-1 expression on CD8+ lymphocytes. These data suggest that homeostatic proliferation of infected cells, an important mechanism for HIV persistence, is an intriguing therapeutic target.

Memory for temporal structure enables both planning of future events and retrospection of past events. We investigated how the brain flexibly represents extended temporal sequences into the past and future during anticipation. Participants learned sequences of environments in immersive virtual reality. Pairs of sequences had the same environments in a different order, enabling context-specific learning. During fMRI, participants anticipated upcoming environments multiple steps into the future in a given sequence. Temporal structure was represented in the hippocampus and across higher-order visual regions (1) bidirectionally, with graded representations into the past and future and (2) hierarchically, with further events into the past and future represented in successively more anterior brain regions. In hippocampus, these bidirectional representations were context-specific, and suppression of far-away environments predicted response time costs in anticipation. Together, this work sheds light on how we flexibly represent sequential structure to enable planning over multiple timescales.

BackgroundDespite elevated rates of trauma exposure, substance misuse, mental health problems, and suicide, systems-impacted teens and their caregivers have limited access to empirically supported behavioral health services. Family-based interventions are the most effective for improving mental health, education, substance use, and delinquency outcomes, yet the familial and placement disruption that occurs during child welfare involvement can interfere with the delivery of family-based interventions.ObjectiveTo address this gap in access to services, we adapted an in-person, empirically supported, family-based affect management intervention using a trauma-informed lens to be delivered via telehealth to families impacted by the child welfare system (Family Telehealth Project). We describe the intervention adaptation process and an open trial to evaluate its feasibility, acceptability, and impact.MethodsAdaptations to the in-person, family-based affect management intervention were conducted iteratively with input from youth, caregivers, and systems partners. Through focus groups and collaborative meetings with systems partners, a caregiver-only version of the intervention was also developed. An open trial of the intervention was conducted to assess family perspectives of its acceptability and feasibility and inform further refinements prior to a larger-scale evaluation. Participants included English-speaking families involved in the child welfare system in the past 12 months with teens (aged 12-18 years). Caregivers were eligible to participate either individually (caregivers of origin, kinship caregivers, or foster parents; n=7) or with their teen (caregiver of origin only; n=6 dyads). Participants completed session feedback forms and surveys at pretreatment, posttreatment, and 3-month posttreatment time points. Qualitative exit interviews were conducted with a subset of participants (12/19, 63%) to further understand their experiences with the intervention.ResultsSession attendance was high, and both caregivers and teens reported high acceptability of clinicians and sessions on feedback forms. Families were comfortable with video technology, with very few (

The skin is complex with multiple layers serving protective, regulatory, and detective functions. The skin hosts chemicals originating from consumption, synthesis, and the environment. Skin chemicals can provide insight into ones daily routine or their level of safety in a work environment. The goal of this study was to investigate the utility of noninvasive skin swabs to detect drugs in a pharmacy setting and to determine whether drugs are transferred to the skin of pharmacy staff. To answer this question, skin swabs were collected from healthy pharmacy staff workers and healthy non-pharmacy individuals and analyzed via untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS). Drugs were annotated through library matching against the GNPS community spectral library. We then used questionnaire data to exclude medications that participants took orally or applied topically and focused on the drugs participants were exposed to in the work setting. Overall, pharmacy staff had a higher number and variety of medications on their skin as compared with healthy individuals who did not work in a pharmacy. In addition, we identified some chemicals such as N,N-Diethyl-metatoluamide on a large number of subjects in both experimental and control groups, indicating environmental exposure to this compound may be ubiquitous and long-lasting.

There is a clinical need for a simple test implementable at the primary point of care to identify individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) in the population. Blood plasma samples from adult patients with varying phenotypes of MASLD were used to identify a minimal set of lipid analytes reflective of underlying histologically confirmed MASLD. Samples were obtained from the NIDDK Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) NAFLD Database prospective cohort study (MASLD group; N = 301). Samples of control subjects were obtained from cohort studies at the University of California San Diego (control group; N = 48). Plasma samples were utilized for targeted quantitation of circulating eicosanoids, related bioactive metabolites, and polyunsaturated fatty acids by ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) lipidomics analysis. Bioinformatic approaches were used to discover a panel of bioactive lipids that can be used as a diagnostic tool to identify MASLD. The final panel of fifteen lipid metabolites consists of 12 eicosanoid metabolites and 3 free fatty acids that were identified to be predictive for MASLD by multivariate area under the receiver operating characteristics curve (AUROC) analysis. The panel was highly predictive for MASLD with an AUROC of 0.999 (95% CI = 0.986-1.0) with only one control misclassified. A validation study confirmed the resulting MASLD LIPIDOMICS SCORE, which may require a larger-scale prospective study to optimize. This predictive model should guide the development of a non-invasive "point-of-care" test to identify MASLD patients requiring further evaluation for the presence of metabolic dysfunction-associated steatohepatitis.

BACKGROUND: Non-ordinary states of consciousness induced by psychedelics can be accompanied by so-called peak experiences, characterized at the emotional level by their intensity and positive valence. These experiences are strong predictors of positive outcomes following psychedelic-assisted therapy, and it is therefore important to better understand their biology. Despite growing evidence that the autonomic nervous system (ANS) plays an important role in mediating emotional experiences, its involvement in the psychedelic experience is poorly understood. The aim of this study was to investigate to what extent changes in the relative influence of the sympathetic (SNS) and parasympathetic nervous systems (PNS) over cardiac activity may reflect the subjective experience induced by the short-acting psychedelic N,N-Dimethyltryptamine (DMT). METHODS: We derived measures of SNS and PNS activity from the electrocardiograms of 17 participants (11 males, mean age = 33.8 years, SD = 8.3) while they received either DMT or placebo. RESULTS: Results show that the joint influence of SNS and PNS (sympathovagal coactivation) over cardiac activity was positively related to participants ratings of Spiritual Experience and Insightfulness during the DMT experience, while also being related to improved well-being scores 2 weeks after the session. In addition, we found that the state of balance between the two ANS branches (sympathovagal balance) before DMT injection predicted scores of Insightfulness during the DMT experience, as well as subsequent sympathovagal coactivation. CONCLUSION: These findings demonstrate the involvement of the ANS in psychedelic-induced peak experiences and may pave the way to the development of biofeedback-based tools to enhance psychedelic therapy.

BACKGROUND: An association between driving pressure (∆P) and the outcomes of invasive mechanical ventilation (IMV) may exist. However, the effect of a sustained limitation of ∆P on mortality in patients with acute respiratory distress syndrome (ARDS), including patients with COVID-19 (COVID-19-related acute respiratory distress syndrome (C-ARDS)) undergoing IMV, has not been rigorously evaluated. The use of emulations of a target trial in intensive care unit research remains in its infancy. To inform future, large ARDS target trials, we explored using a target trial emulation approach to analyse data from a cohort of IMV adults with C-ARDS to determine whether maintaining daily ∆p24 hours of IMV were considered to be assigned to limited ∆P or LTVV. Lung mechanics were measured twice daily after ventilator setting adjustments were made. To evaluate the effect of each lung-protective ventilation (LPV) strategy on the 28-day mortality, we fit a stabilised inverse probability weighted marginal structural model that adjusted for baseline and time-varying confounders known to affect protection strategy use/adherence or survival. RESULTS: Among the 92 patients included, 27 (29.3%) followed limited ∆P ventilation, 23 (25.0%) the LTVV strategy and 42 (45.7%) received no LPV strategy. The adjusted estimated 28-day survival was 47.0% (95% CI 23%, 76%) in the limited ∆P group, 70.3% in the LTVV group (95% CI 37.6%, 100%) and 37.6% (95% CI 20.8%, 58.0%) in the no LPV strategy group. INTERPRETATION: Limiting ∆P may not provide additional survival benefits for patients with C-ARDS over LTVV. Our results help inform the development of future target trial emulations focused on evaluating LPV strategies, including reduced ∆P, in adults with ARDS.

BACKGROUND: Invasive lobular carcinoma (ILC) of the breast grows in a diffuse pattern, resulting in a high risk of positive margins at surgical resection. Oncoplastic approaches have been shown to reduce this risk, but concerns persist around the safety of immediate oncoplastic surgery for those with ILC. This study evaluated the short- and long-term oncologic outcomes of immediate oncoplastic surgery for patients with ILC. METHODS: This study retrospectively analyzed an institutional database of stages I to III ILC patients who underwent breast-conserving surgery (BCS) with or without immediate oncoplastic surgery (oncoplastic closure or oncoplastic reduction mammoplasty [ORM]). The study compared positive margin rates, rates of successful BCS, and recurrence-free survival (RFS) by type of surgery. RESULTS: For 494 patients the findings showed that the use of immediate ORM was associated with significantly lower odds of positive margins (odds ratio [OR], 0.34; 95 % confidence interval [CI], 0.17-0.66; p = 0.002). Both lumpectomy with oncoplastic closure and ORM were significantly associated with higher rates of successful BCS than standard lumpectomy (94.2 %, 87.8 %, and 73.9 %, respectively; p < 0.001). No difference in RFS was observed between those undergoing immediate oncoplastic surgery and those undergoing standard lumpectomy alone. CONCLUSIONS: The patients with stages I to III ILC who underwent immediate oncoplastic surgery had significant benefits including lower odds of positive margins and higher rates of successful BCS, with both types of immediate oncoplastic surgery showing similar RFS compared with lumpectomy alone. This supports the oncologic safety of immediate oncoplastic surgery for diffusely growing tumors such as ILC, providing it an ideal option for patients desiring BCS.

Crohn's disease (CD) is a complex and heterogeneous condition with no perfect preclinical model or cure. To address this, we explore adult stem cell-derived organoids that retain their tissue identity and disease-driving traits. We prospectively create a biobank of CD patient-derived organoid cultures (PDOs) from colonic biopsies of 53 subjects across all clinical subtypes and healthy subjects. Gene expression analyses enabled benchmarking of PDOs as tools for modeling the colonic epithelium in active disease and identified two major molecular subtypes: immune-deficient infectious CD (IDICD) and stress and senescence-induced fibrostenotic CD (S2FCD). Each subtype shows internal consistency in the transcriptome, genome, and phenome. The spectrum of morphometric, phenotypic, and functional changes within the "living biobank" reveals distinct differences between the molecular subtypes. Drug screens reverse subtype-specific phenotypes, suggesting phenotyped-genotyped CD PDOs can bridge basic biology and patient trials by enabling preclinical phase "0" human trials for personalized therapeutics.

PURPOSE: Nuclear protein in testis carcinoma (NC) is an underdiagnosed and aggressive squamous/poorly differentiated cancer characterized by rearrangement of the gene NUTM1 on chromosome 15q14. Co-occurring alternations have not been fully characterized. METHODS: We analyzed the genomic and immune landscape of 54 cases of NC that underwent DNA- and RNA-based NGS sequencing (Caris). RESULTS: While NC is driven by NUTM1 fusion oncoproteins, co-occurring DNA mutations in epigenetic or cell cycle pathways were observed in 26% of cases. There was no significant difference between the fusion partner of NUTM1 and co-occurring gene mutations. RNA sequencing analysis showed increased MYC pathway activity in NC compared with head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma (LUSC), which is consistent with the known pathophysiology of NC. Characterization of the NC tumor microenvironment using RNA sequencing revealed significantly lower immune cell infiltration compared with HNSCC and LUSC. NC was 10× higher in patients with HNSCC and LUSC younger than 50 years than in those older than 70 years. CONCLUSION: To our knowledge, this is the first series of NC profiled broadly at the DNA and RNA level. We observed fewer intratumoral immune cells by RNA sequencing, which may be associated with anecdotal data of lack of immunotherapy benefit in NC. High MYC pathway activity in NC supports ongoing trials targeting MYC suppression. The incidence of NC among patients younger than 50 years with LUSC/HNSCC supports testing for NC in these patients. The prognosis of NCs remains dismal, and future studies should focus on improving the response to immunotherapy and targeting MYC.

Self-control plays a pivotal role in pursuing long-term goals related to health and financial well-being. While ample evidence suggests that humans are prone to occasional self-control lapses, little is known about how changes in emotional and attentional states affect the ability to maintain self-control. In two studies (N1 = 109 and N2 = 90), we used emotion recognition software to decode participants' facial expressions while manipulating their attentional and emotional states during a Psychomotor Vigilance Task (PVT) before exerting self-control in a subsequent task. Our findings reveal dissociable roles of attention and valence in maintaining self-control, depending on the distinct demands of the task. Specifically, performance in a subsequent cognitive task was predominantly associated with changes in attentional states during the PVT rather than valence. Conversely, preferences in a subsequent social task were associated with changes in valence states during the PVT, while attention showed no effect. This dissociation between attention-invoked and emotion-invoked lapses in self-control holds significant implications for psychological and economic models of self-control, ultimately contributing to the development of policies to mitigate the detrimental consequences of individual self-control lapses.

BACKGROUND: Invasive lobular carcinoma (ILC) is the second most common subtype of breast cancer. Although mammography is known to have low sensitivity for ILC, there are no data to guide the optimal surveillance after treatment. We explored surveillance strategies after breast-conserving surgery (BCS) for ILC and determined the proportion of imaging-detected recurrences versus interval cancers. METHODS: From an institutional database of 813 women, we retrospectively identified patients who underwent BCS for stage I-III ILC and subsequently had a recurrence. We categorized patients by surveillance strategy and determined the modality of recurrence detection. Interval cancer rates for local recurrences were compared across surveillance strategies using the Chi-square test. We evaluated overall survival with the log-rank test and a Cox proportional hazards model. RESULTS: We included 58 patients with ILC who had a recurrence after BCS. Of these, 22 (37.9%) had local recurrence, 27 (46.6%) had distant recurrence, and 9 (15.5%) had both local and distant recurrence. Most patients underwent routine mammographic surveillance (65.2%), with 19.6% having supplemental breast magnetic resonance imaging (MRI) and 15.2% having no surveillance. The interval cancer rate was significantly higher in the mammographic surveillance group compared with the MRI surveillance group (61.9% vs. 16.7%; p

BackgroundDual use of both e-cigarettes and cigarettes is popular among young adults and may lead to greater nicotine dependence and additive adverse health effects than single-product use. However, existing cessation programs target quitting either e-cigarettes or cigarettes, highlighting a need for interventions to help young adults quit both products (ie, dual tobacco cessation).ObjectiveThis formative study is part of a larger project to develop a smartphone intervention for dual tobacco cessation among young adults. This study aimed to (1) explore desires for and experiences with quitting both e-cigarettes and cigarettes and (2) identify needs and preferences for dual tobacco cessation intervention programming.MethodsSemistructured interviews were conducted to elicit the need for and experience with dual tobacco cessation among 14 young adults (18-29 years old) recruited through Instagram (Meta) advertisements in 2023. We conducted a thematic analysis to identify common themes related to quitting experiences and cessation needs.ResultsParticipants expressed a strong desire for dual tobacco cessation and had attempted to quit both tobacco products, mostly "cold turkey." The priority product for quitting first varied by the individual's perceived harm or level of consumption. Targets for dual tobacco cessation interventions included (1) highlighting the health effects of dual tobacco use compared with single product use, (2) providing cessation support to quit one prioritized product while cutting down the other product with the explicit goal to quit both, (3) emphasizing unique facilitators and barriers to quitting each product (eg, unpleasant smell of cigarettes facilitating smoking cessation and accessibility and flavors of e-cigarettes hindering vaping cessation), and (4) addressing co-use of tobacco with alcohol or cannabis. Participants wanted personalized interventions through smartphone apps that would tailor support to their tobacco use patterns and unique quitting goals and needs. They also suggested presenting intervention content in multimedia (eg, videos, graphic pictures, quizzes, and games) to increase engagement.ConclusionsThis study provides important insights into young adults' experiences, needs, and preferences for dual tobacco product cessation. We highlight important targets for future smartphone apps to deliver personalized and tailored support to meet the heterogeneous needs and preferences of young people who want to quit using both e-cigarettes and cigarettes.

BACKGROUND: For patients with clinically node-positive (cN+) breast cancer undergoing neoadjuvant chemotherapy (NAC), retrieving previously clipped, biopsy-proven positive lymph nodes during sentinel lymph node biopsy [i.e., targeted axillary dissection (TAD)] may reduce false negative rates. However, the overall utilization and impact of clipping positive nodes remains uncertain. PATIENTS AND METHODS: We retrospectively analyzed cN+ ISPY-2 patients (2011-2022) undergoing axillary surgery after NAC. We evaluated trends in node clipping and associations with type of axillary surgery [sentinel lymph node (SLN) only, SLN and axillary lymph node dissection (ALND), or ALND only] and event-free survival (EFS) in patients that were cN+ on a NAC trial. RESULTS: Among 801 cN+ patients, 161 (20.1%) had pre-NAC clip placement in the positive node. The proportion of patients that were cN+ undergoing clip placement increased from 2.4 to 36.2% between 2011 and 2021. Multivariable logistic regression showed nodal clipping was independently associated with higher odds of SLN-only surgery [odds ratio (OR) 4.3, 95% confidence interval (CI) 2.8-6.8, p < 0.001]. This was also true among patients with residual pathologically node-positive (pN+) disease. Completion ALND rate did not differ based on clip retrieval success. No significant differences in EFS were observed in those with or without clip placement, both with or without successful clip retrieval [hazard ratio (HR) 0.85, 95% CI 0.4-1.7, p = 0.7; HR 1.8, 95% CI 0.5-6.0, p = 0.3, respectively]. CONCLUSION: Clip placement in the positive lymph node before NAC is increasingly common. The significant association between clip placement and omission of axillary dissection, even among patients with pN+ disease, suggests a paradigm shift toward TAD as a definitive surgical management strategy in patients with pN+ disease after NAC.

INTRODUCTION: Expanding access to doula care is a key strategy for improving the perinatal experiences and health outcomes of birthing people of color in the U.S. This study investigates the future of maternal healthcare in the U.S. from the perspective of doulas and highlights emerging technology and other opportunities related to strengthening the doula workforce. METHODS: The study recruited community doulas from 12 unique U.S. states, ensuring at least half of the doulas predominantly served communities of color. Doulas (N = 26) participated in semi-structured, futures-oriented interviews that explored their experiences providing care during the COVID-19 pandemic and utilization of technology. A subset of doulas (n = 8) were engaged in interactive workshops where they envisioned alternative futures for doula care and childbirth. Interviews and workshops were analyzed using the Framework Method. RESULTS: The COVID-19 pandemic heightened technology use among doulas and increased client accessibility. Social media serves as a unique space for critical community building and client outreach. Doulas reported opportunities to strengthen and mobilize the future workforce: recognizing doula care as a reimbursable service by health insurers, utilizing doula collectives for community practice to decrease burnout, increasing emotional support for doulas, and instilling a chain of learning through mentorship. DISCUSSION: Futures thinking served as a valuable approach for doulas to illuminate the implications of present-day challenges and empowered doulas to design roadmaps toward better futures for doulas and maternal health. Doulas should be engaged as partners to hold a meaningful decision-making role when discussing policies, employment structures, emerging technology, and other aspects of doulas positioning within the healthcare system.

Youth Mental Health First Aid (YMHFA) trains individuals who regularly interact with youth to identify youth experiencing mental health challenges. Several studies demonstrate positive training impacts, but few assess whether the training equally impacts participants of different demographic and professional backgrounds or those who participate in different training modalities. Using a pre-post follow-up design with a comparison group, this study examined changes in participants confidence in their ability to recognize and support youth mental health needs 1 to 2 months after training. Data were collected over two years (2021-2023) from training participants (n = 480) and comparable non-participants (n = 51). The authors examined whether changes in confidence varied by participant race/ethnicity, professional role in the education or mental health fields, and training modality (online versus hybrid). Training participants confidence in supporting youth mental health increased significantly compared to non-participants. Although the training was effective for all participants, those with less mental health experience benefited more, consistent with previous research. While both in-person and hybrid training were effective, in-person training participants reported slightly higher confidence scores than virtual at follow-up. Study findings suggest that educational and social service organizations should offer this training to their staff and community members who interact with youth, prioritizing participants with less prior mental health training and delivering training through an in-person training modality when possible. However, additional research is needed to explore how aspects of in-person training, such as trainer characteristics and group dynamics, impact outcomes.

The functional Scale for the Assessment and Rating of Ataxia (f-SARA) assesses Gait, Stance, Sitting, and Speech. It was developed as a potentially clinically meaningful measure of spinocerebellar ataxia (SCA) progression for clinical trial use. Here, we evaluated content validity of the f-SARA. Qualitative interviews were conducted among individuals with SCA1 (n = 1) and SCA3 (n = 6) and healthcare professionals (HCPs) with SCA expertise (USA, n = 5; Europe, n = 3). Interviews evaluated symptoms and signs of SCA and relevance of f-SARA concepts for SCA. HCP cognitive debriefing was conducted. Interviews were recorded, transcribed, coded, and analyzed by ATLAS.TI software. Individuals with SCA1 and 3 reported 85 symptoms, signs, and impacts of SCA. All indicated difficulties with walking, stance, balance, speech, fatigue, emotions, and work. All individuals with SCA1 and 3 considered Gait, Stance, and Speech relevant f-SARA concepts; 3 considered Sitting relevant (42.9%). All HCPs considered Gait and Speech relevant; 5 (62.5%) indicated Stance was relevant. Sitting was considered a late-stage disease indicator. Most HCPs suggested inclusion of appendicular items would enhance clinical relevance. Cognitive debriefing supported clarity and comprehension of f-SARA. Maintaining current abilities on f-SARA items for 1 year was considered meaningful for most individuals with SCA1 and 3. All HCPs considered meaningful changes as stability in f-SARA score over 1-2 years, 1-2-point change in total f-SARA score, and deviation from natural history. These results support content validity of f-SARA for assessing SCA disease progression in clinical trials.

OBJECTIVE: To evaluate the reliability, responsiveness, and validity of the Scale for the Assessment and Rating of Ataxia (SARA) in patients with lysosomal storage disorders (LSDs) who present with neurological symptoms, and quantify the threshold for a clinically meaningful change. METHODS: We analyzed data from three clinical trial cohorts (IB1001-201, IB1001-202, and IB1001-301) of patients with Niemann-Pick disease type C (NPC) and GM2 Gangliosidoses (Tay-Sachs and Sandhoff disease) comprising 122 patients and 703 visits. Reproducibility was described as re-test reliability between repeat baseline visits or baseline and post-treatment washout visits. Responsiveness was determined in relation to the Investigators, Caregivers, and Patients Clinical Global Impression of Improvement (CGI-I). The CGI-I data was also used to quantify a threshold for a clinically meaningful improvement on the SARA scale. Using a qualitative methods approach, patient/caregiver interviews from the IB1001-301 trial were further used to assess a threshold of meaningful change as well as the breadth of neurological signs and symptoms captured and evaluated by the SARA scale. RESULTS: The Inter-Class Correlation (ICC) was 0.95 or greater for all three trials, indicating a high internal consistency/reliability. The mean change in SARA between repeat baseline and post-treatment washout visit assessments in all trials was -0.05, SD 1.98, i.e., minimal, indicating no significant differences, learning effects or other systematic biases. For the CGI-I responses and change in SARA scores, Area Under the Curve (AUC) values were 0.82, 0.71, and 0.77 for the Investigators, Caregivers, and Patients CGI-I respectively, indicating strong agreement. Further qualitative analyses of the patient/caregiver interviews demonstrated a 1-point or greater change on SARA to be a clinically meaningful improvement which is directly relevant to the patients everyday functioning and quality of life. Changes captured by the SARA were also paralleled by improvement in a broad range of neurological signs and symptoms and beyond cerebellar ataxia. CONCLUSION: Qualitative and quantitative data demonstrate the reliability and responsiveness of the SARA score as a valid measure of neurological signs and symptoms in LSDs with CNS involvement, such as NPC and GM2 Gangliosidoses. A 1-point change represents a clinically meaningful transition reflecting the gain or loss of complex function.

Hazardous alcohol consumption is highly prevalent for men who have sex with men (MSM). The 4 treatments currently approved by the Food and Drug Administration for alcohol use are reaching an alarmingly low percentage of people who would benefit from a reduction in their alcohol use. There is increasing interest in alternative methods of treatment, such as herbal supplements, to address hazardous drinking. However, research on the acceptability of alternative pharmacotherapies among MSM remains limited. We examined the prevalence and correlates of expressing interest in using herbal supplements for alcohol treatment among MSM with hazardous alcohol consumption. We conducted a secondary data analysis from a cross-sectional study of MSM who use alcohol, conducted from March 2015 to July 2017 in San Francisco, California, to assess the overall prevalence of interest in using herbal supplements to help reduce alcohol consumption. Associations between expressing interest in herbal supplements and demographic, social, and clinical characteristics were examined using bivariate and multivariable logistic regression models. One-third (66/200, 33%) of the participants expressed interest in an herbal supplement for reducing alcohol consumption. In the multivariable analyses, weekly binge drinking (adjusted odds ratio [aOR] 2.85, 95% CI 1.17-6.93), interest in abstaining from alcohol use (aOR 5.04, 95% CI 1.46-17.40), higher severity of alcohol dependence score (aOR 1.22, 95% CI 1.04-1.41), and interest in naltrexone (aOR 3.22, 95% CI 2.12-4.91) were independently associated with higher odds of being interested in using an herbal supplement to reduce alcohol consumption, adjusting for age, race or ethnicity, and education. We found that MSM who have hazardous drinking habits, more severe alcohol dependence, and interest in pharmacotherapy were more likely to express interest in using an herbal supplement for reducing alcohol consumption. To our knowledge, this is the first study that has evaluated correlates of interest in herbal supplements for alcohol use among MSM. As researchers implement novel alcohol treatment studies, they should focus on recruitment efforts among MSM with a motivation to reduce their alcohol use patterns.

Insomnia and pain disorders are among the most common conditions affecting United States adults and veterans, and their comorbidity can cause detrimental effects to quality of life among other factors. Cognitive behavioural therapy for insomnia and related behavioural therapies are recommended treatments for insomnia, but chronic pain may hinder treatment benefit. Prior research has not addressed how pain impacts the effects of behavioural insomnia treatment in United States women veterans. Using data from a comparative effectiveness clinical trial of two insomnia behavioural treatments (both including sleep restriction, stimulus control, and sleep hygiene education), we examined the impact of pain severity and pain interference on sleep improvements from baseline to post-treatment and 3-month follow-up. We found no significant moderation effects of pain severity or interference in the relationship between treatment phase and sleep outcomes. Findings highlight opportunities for using behavioural sleep interventions in patients, particularly women veterans, with comorbid pain and insomnia, and highlight areas for future research.

Nearly 10% of pregnant women suffer traumatic injury. Clinical outcomes for pregnant trauma patients (PTPs) with severe injuries have not been well studied. We sought to describe outcomes for PTPs presenting with severe injuries, hypothesizing that PTPs with severe injuries will have higher rates of complications and mortality compared to less injured PTPs. A post-hoc analysis of a multi-institutional retrospective study at 12 Level-I/II trauma centers was performed. Patients were stratified into severely injured (injury severity score [ISS] > 15) and not severely injured (ISS

We proposed an end-to-end deep learning convolutional neural network (DCNN) for region-of-interest based multi-parameter quantification (RMQ-Net) to accelerate quantitative ultrashort echo time (UTE) MRI of the knee joint with automatic multi-tissue segmentation and relaxometry mapping. The study involved UTE-based T1 (UTE-T1) and Adiabatic T1ρ (UTE-AdiabT1ρ) mapping of the knee joint of 65 human subjects, including 20 normal controls, 29 with doubtful-minimal osteoarthritis (OA), and 16 with moderate-severe OA. Comparison studies were performed on UTE-T1 and UTE-AdiabT1ρ measurements using 100%, 43%, 26%, and 18% UTE MRI data as the inputs and the effects on the prediction quality of the RMQ-Net. The RMQ-net was modified and retrained accordingly with different combinations of inputs. Both ROI-based and voxel-based Pearson correlation analyses were performed. High Pearson correlation coefficients were achieved between the RMQ-Net predicted UTE-T1 and UTE-AdiabT1ρ results and the ground truth for segmented cartilage with acceleration factors ranging from 2.3 to 5.7. With an acceleration factor of 5.7, the Pearson r-value achieved 0.908 (ROI-based) and 0.945 (voxel-based) for UTE-T1, and 0.733 (ROI-based) and 0.895 (voxel-based) for UTE-AdiabT1ρ, correspondingly. The results demonstrated that RMQ-net can significantly accelerate quantitative UTE imaging with automated segmentation of articular cartilage in the knee joint.

Spinocerebellar ataxias (SCA) are rare inherited neurodegenerative disorders characterized by a progressive impairment of gait, balance, limb coordination, and speech. There is currently no composite scale that includes multiple aspects of the SCA experience to assess disease progression and treatment effects. Applying the method of partial least squares (PLS) regression, we developed the Spinocerebellar Ataxia Composite Scale (SCACOMS) from two SCA natural history datasets (NCT01060371, NCT02440763). PLS regression selected items based on their ability to detect clinical decline, with optimized weights based on the items degree of progression. Following model validation, SCACOMS was leveraged to examine disease progression and treatment effects in a 48-week SCA clinical trial cohort (NCT03701399). Items from the Clinical Global Impression-Global Improvement Scale (CGI-I), the Friedreich Ataxia Rating Scale (FARS) - functional stage, and the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) were objectively selected with weightings based on their sensitivity to clinical decline. The resulting SCACOMS exhibited improved sensitivity to disease progression and greater treatment effects (compared to the original scales from which they were derived) in a 48-week clinical trial of a novel therapeutic agent. The trial analyses also provided a SCACOMS-derived estimate of the temporal delay in SCA disease progression. SCACOMS is a useful composite measure, effectively capturing disease progression and highlighting treatment effects in patients with SCA. SCACOMS will be a powerful tool in future studies given its sensitivity to clinical decline and ability to detect a meaningful clinical impact of disease-modifying treatments.

PURPOSE: To describe U-type sacral fracture characteristics amenable to percutaneous sacral screw fixation. METHODS: U-type sacral fractures were identified from a trauma registry at a level 1 trauma center from 2014 to 2020. Patient demographics, injury mechanism, fracture characteristics, and fixation construct were retrospectively retrieved. Associations between fracture pattern and surgical fixation were identified. RESULTS: 82 U-type sacral fractures were reviewed. Six treated with lumbopelvic fixation (LPF) and 76 were treated with percutaneous sacral screws (PSS) alone. Patients receiving LBF had greater sacral fracture displacement in coronal, sagittal, and axial planes compared to patients receiving PSS alone (P

This post hoc analysis of the randomized, placebo-controlled N-MOmentum study (NCT02200770) of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD) evaluated relationships between circulating B-cell subsets and aquaporin-4 immunoglobulin G (AQP4-lgG) titers and attacks. Among participants receiving placebo, CD20+ and CD27+ B-cell counts were modestly increased from the pre-attack visit to attack; plasmablast/plasma cell gene signature was increased from baseline to the pre-attack visit (p = 0.016) and from baseline to attack (p = 0.009). With inebilizumab treatment, B-cell subset counts decreased and did not increase with attacks. No difference in change of AQP4-IgG titers from baseline to time of attack was observed.

People are often presented with large amounts of information to remember, and in many cases, the font size of information may be indicative of its importance (such as headlines or warnings). In the present study, we examined how learners perceive the importance of information in different font sizes and how beliefs about font size influence selective memory. In Experiment 1, participants were presented with to-be-remembered words that were either unrelated or related to a goal (e.g., items for a camping trip) in either small or large font. Participants rated words in large font as more important to remember than words in small font when the words in a list were unrelated but not when the words were schematically related to a goal. In Experiments 2 and 3, we were interested in how learners belief that font size is indicative of importance translates to their ability to selectively encode and recall valuable information. Specifically, we presented participants with words in various font sizes, and larger fonts either corresponded to greater point values or smaller point values (values counted towards participants scores if recalled). When larger fonts corresponded with greater point values, participants were better able to selectively remember high-value words relative to low-value words. Thus, when to-be-remembered information varies in value, font size may be less diagnostic of an items importance (the items importance drives memory), and when the value of information is consistent with a learners belief, learners can better engage in selective memory.

BACKGROUND: A growing literature suggests associations between occupational pesticide exposure and respiratory health. In this study, we aimed to examine the association of exposure to insecticides, fungicides, and herbicides, individually and as a mixture, with respiratory health outcomes and rhinitis in avocado farmworkers from Michoacán, Mexico. MATERIAL AND METHODS: We conducted a cross-sectional study of 105 avocado farmworkers between May and August 2021. We quantified 12 insecticide, fungicide, and herbicide metabolites in urine samples collected during two study visits (8-10 weeks apart). We collected survey data on self-reported pesticide use during the 12 months prior to the baseline survey and estimated annual exposure-intensity scores (EIS) using a semi-quantitative exposure algorithm. We also assessed respiratory symptoms, including wheezing, chest tightness, wheezing after exercise, and night cough. We used generalized linear regression models to examine associations of individual urinary metabolite concentrations and annual EIS with respiratory health outcomes and rhinitis. Mixture effects were assessed using Bayesian Weighted Quantile Sum (BWQS) regression. RESULTS: After adjusting for multiple comparisons, we observed mostly null associations of individual pesticide metabolite concentrations and annual EIS with the outcomes of interest. However, in BWQS analyses, we found evidence of a mixture association of urinary pesticide metabolites with increased odds of night cough (OR: 5.34, 95 % CrI: 1.67, 20.62). Pyrethroid metabolites 3-phenoxybenzoic acid and cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid were the main contributors to this association (43 %). CONCLUSIONS: Our findings indicate that exposure to a mixture of pesticides, particularly pyrethroid insecticides, may be associated with night cough in avocado farmworkers.

UNLABELLED: A common complication of chimeric antigen receptor (CAR) T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS), which presents with encephalopathy, aphasia, inattention, somnolence, seizures, weakness, or cerebral edema. Despite its significant morbidity, there are currently no effective targeted treatments. Given the clinical similarities between ICANS and the neurological manifestations of acute hypophosphatemia, we retrospectively reviewed 499 patients treated with CD19-targeted CAR T-cell therapy across multiple clinical trials between 2015 and 2020. In addition to clinical toxicities experienced by the patients, we also interrogated the impact of serum electrolyte data and repletion of corresponding electrolyte deficiencies with ICANS incidence, severity, and duration. Hypophosphatemia was a common occurrence in CAR T-cell recipients and the only electrolyte derangement associated with a significantly higher cumulative incidence of ICANS. Moreover, phosphorus repletion in patients with hypophosphatemia was associated with significantly decreased ICANS incidence and duration. Hypophosphatemia was uniquely associated with encephalopathy neurological adverse events, which also showed the strongest positive correlation with both ICANS and cytokine release syndrome severity. These findings suggest that serum phosphorus could be a reliable biomarker for ICANS, and expeditious, goal-directed phosphorus repletion in response to serum hypophosphatemia could be a safe, inexpensive, and widely available intervention for such patients. SIGNIFICANCE: Herein we show that phosphorus repletion in patients with hypophosphatemia receiving anti-CD19 chimeric antigen receptor T-cell therapeutics was associated with significantly decreased immune effector cell-associated neurotoxicity syndrome (ICANS) incidence and symptom duration. Given the significant morbidity associated with ICANS and lack of targeted interventions, hypophosphatemia may serve as both a useful biomarker and an inexpensive intervention for ICANS.

Ataxia with anti-regulator of G-protein signaling 8 autoantibodies (RGS8-Abs) is an autoimmune disease recently described in four patients. The present study aimed to identify other patients with RGS8-Abs, describe their clinical features, including the link between RGS8-related autoimmune cerebellar ataxia (ACA) and cancer. Patients with RGS8-Abs were identified retrospectively in the biological collections of the French Reference Center for Paraneoplastic Neurological Syndrome and the University of California San Francisco Center for Encephalitis and Meningitis. Clinical data were collected, and cerebrospinal fluid, serum, and tumor pathological samples were retrieved to characterize the autoantibodies and the associated malignancies. Only three patients with RGS8-Abs were identified. All of them presented with a pure cerebellar ataxia of mild to severe course, unresponsive to current immunotherapy regimens for ACA. Two patients presented with a Hodgkin lymphoma of the rare specific subtype called nodular lymphocyte-predominant Hodgkin lymphoma, with very mild extension. Autoantibodies detected in all patients enriched the same epitope on the RGS8 protein, which is an intracellular protein physiologically expressed in Purkinje cells but also ectopically expressed specifically in lymphoma cells of patients with RGS8-related ACA. The present results and those of the four cases previously described suggest that RGS8-Abs define a new paraneoplastic neurological syndrome of extreme rarity found mostly in middle-aged males that associates pure cerebellar ataxia and a particular lymphoma specifically expressing the RGS8 antigen. As in other paraneoplastic ACA with intracellular antigen, the disease course is severe, and patients tend to exhibit a poor response to immune therapy.

BackgroundThe Mnemonic Similarity Task (MST) is a popular memory task designed to assess hippocampal integrity. We assessed whether analyzing MST performance using a multinomial processing tree (MPT) cognitive model could detect individuals with elevated Alzheimer's disease (AD) biomarker status prior to cognitive decline.MethodWe analyzed MST data from >200 individuals (young, cognitively healthy older adults and individuals with mild cognitive impairment [MCI]), a subset of which also had existing cerebrospinal fluid (CSF) amyloid beta (Aβ) and phosphorylated tau (pTau) data using both traditional and model-derived approaches. We assessed how well each could predict age group, memory ability, MCI status, Aβ, and pTau status using receiver operating characteristic analyses.ResultsBoth approaches predicted age group membership equally, but MPT-derived metrics exceeded traditional metrics in all other comparisons.DiscussionA MPT model of the MST can detect individuals with AD prior to cognitive decline, making it a potentially useful tool for screening and monitoring older adults during the asymptomatic phase of AD.HighlightsThe MST, along with cognitive modeling, identifies individuals with memory deficits and cognitive impairment. Cognitive modeling of the MST identifies individuals with increased AD biomarkers prior to changes in cognitive function. The MST is a digital biomarker that identifies individuals at high risk of AD.

BACKGROUND: Previous studies have suggested differences in multiple sclerosis (MS) severity according to ethnicity. METHODS: Data were obtained from the UK MS Register, a prospective longitudinal cohort study of persons with MS. We examined the association between self-reported ethnic background and age at onset, symptom of onset and a variety of participant-reported severity measures. We used adjusted multivariable linear regression models to explore the association between ethnicity and impact of MS, and Cox proportional hazards models to assess disability progression. RESULTS: We analysed data from 17,314 people with MS, including participants from self-reported Black (n = 157) or South Asian (n = 230) ethnic backgrounds. Age at MS onset and diagnosis was lower in those of South Asian (median 30.0) and Black (median 33.0) ethnicity compared with White ethnicity (median 35.0). In participants with online MS severity measures available, we found no statistically significant evidence for an association between ethnic background and physical disability in MS in both cross-sectional and longitudinal analyses. CONCLUSION: We found no association between ethnic background and MS severity in a large, diverse UK cohort. These findings suggest that other factors, such as socioeconomic status and structural inequalities, may explain previous findings.