Examining Heart Failure Outcomes Amidst Housing Insecurity.

BACKGROUND: How housing insecurity might affect patients with heart failure (HF) is not well characterized. Housing insecurity increases risks related to both communicable and non-communicable diseases. For patients with HF, housing insecurity likely increases the risk for worse outcomes and rehospitalizations. METHODS AND RESULTS: We analyzed U.S. HF hospitalizations using the 2020 National Inpatient Sample (NIS) and Nationwide Readmissions Database (NRD) to evaluate the impacts of housing insecurity on HF outcomes and hospital utilization. Individuals were identified as having housing insecurity using diagnostic ICD-10 codes. Demographics and comorbidities were compared between HF patients with and without housing insecurity. An adjusted logistic regression was performed to evaluate the relationships between housing insecurity and socioeconomic status on in-hospital mortality. Using a Cox proportional hazards model, HF patients with and without housing insecurity were evaluated for the risk of all-cause and HF-specific readmissions over time. Of the 1,003,270 hospitalizations for HF in the U.S. in 2020, 16,150 were identified as having housing insecurity (1.6%) and 987,120 were identified as having no housing insecurity (98.4%). The median age of patients with housing insecurity hospitalized for HF was 57, as compared to 73 in the population with no housing insecurity. A higher proportion of patients in the housing insecurity group were Black (35% vs 20.1%) or Hispanic (11.1% vs 7.3%). Patients with housing insecurity were more likely to carry a diagnosis of alcohol use disorder (15.2% vs 3.3%) or substance use disorder (70.2% vs 17.8%), but were less likely to use tobacco (18.3% vs 28.7%). Patients with housing insecurity were over 4.5 times more likely to have Medicaid (52.4% vs 11.3%). Median length of stay did not differ between patients with housing insecurity versus those without. Patients with housing insecurity were more likely to discharge Against Medical Advice (11.4% vs 2.03%). After adjusting for patient characteristics, housing insecurity was associated with lower in-hospital mortality (OR 0.60, 95% CI 0.39 - 0.92). Housing insecurity was associated with a higher risk of all-cause readmissions at 180 days (HR 1.13, 95% CI 1.12 - 1.14). However, there was no significant difference in the risk of HF-specific readmissions at 180 days (HR 1.07, 95% CI 0.998 - 1.14) CONCLUSIONS: Patients with HF and housing insecurity have distinct demographic characteristics. They are also more likely to be readmitted after their initial hospitalization when compared to those without housing insecurity. Identifying and addressing specific comorbid conditions for patients with housing insecurity who are hospitalized for HF may allow clinicians to provide more focused care, with the goal of preventing morbidity, mortality, and unnecessary readmissions.

Contextual coherence increases perceived numerosity independent of semantic content.

Number perception emerges from multiple stages of visual processing. Understanding how systematic biases in number perception occur within a hierarchy of increasingly complex feature representations helps uncover the multistage processing underlying our visual number sense. Recent work demonstrated that reducing coherence of low-level visual attributes, such as color and orientation, systematically reduces perceived number. Here, we ask when in the visual processing hierarchy coherence affects numerosity perception and specifically whether the coherence effect is exclusive to low-level visual features or instead whether it can be driven by contextual or semantic relationships. We tested adults in an ordinal numerical comparison task with contextual coherence mathematically manipulated using a statistical model of visual object co-occurrence. Across several experiments, we found that arrays with high contextual coherence were perceived as numerically larger than arrays with low contextual coherence. This contextual coherence effect was not attenuated even when we reduced objects to texforms (unrecognizable images that preserve midlevel visual features) or removed semantic content from the images through box scrambling and diffeomorphic warping. Together, these results suggest that visual coherence derived from natural statistics of object co-occurrence systematically alters perceived numerosity at low-level visual processing, even before later stages at which items can be explicitly categorized and identified. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Dupilumab improves pruritus and skin lesions in patients with prurigo nodularis: Pooled results from 2 phase 3 trials (LIBERTY-PN PRIME and PRIME2).

Background: Phase 3 PRIME/PRIME2 trials independently demonstrated efficacy and an acceptable safety profile of dupilumab adults with moderate-to-severe prurigo nodularis. Objective: To obtain a more precise estimate of onset and magnitude of treatment effect using PRIME/PRIME2 pooled data. Methods: In PRIME/PRIME2, patients were randomized to dupilumab or placebo for 24 weeks. Pooled analysis assessed proportion of patients achieving clinically meaningful improvement in itch, clear/almost-clear skin, or both; at weeks 12 and 24; overall and by demographic subgroups and changes from baseline to week 24 in symptoms, signs, and quality of life. Results: Patients receiving dupilumab (n = 153) vs placebo (n = 158) experienced significant improvements in all tested endpoints. At week 24, 90 (58.8%) dupilumab-treated vs 30 (19.0%) placebo-treated patients achieved clinically meaningful improvement in itch, 71 (46.4%) vs 27 (17.1%) clear/almost clear skin, and 54 (35.3%) vs 14 (8.9%) achieved both (P < .0001 for all). Treatment benefits were independent of baseline demographics. Safety to week 36 was generally consistent with the known dupilumab safety profile. Limitations: On-treatment data limited to 24 weeks. Conclusions: Pooled analysis confirmed improvements reported in individual trials and revealed earlier effect onset in itch and skin pain. Dupilumab treatment showed benefits across demographics.

Evaluation of education initiatives to increase delivery of age-friendly care in retail clinics.

BACKGROUND: The Age-Friendly Health Systems model, encompassing four key elements (4Ms)-What Matters, Medication, Mentation, Mobility-is integral to delivering high-quality care to older adult patients. In May 2020, the MinuteClinic at CVS implemented the 4Ms model in all 1100+ store locations nationwide. To prepare healthcare providers to deliver 4Ms care, educational modules were developed to provide an understanding of the gerontology principles that support the 4Ms model of care. Our goal was to evaluate the effectiveness of these education modules on improving reliable 4Ms delivery during retail clinic visits. METHODS: Educational modules were provided to nurse practitioners and physician associates to complete in a self-directed manner. These included an orientation module with scenarios comparing usual care and 4Ms care, 12 monthly grand rounds focusing on 4Ms case studies, and 10 video vignettes on 4Ms integration. We examined the association between number of education modules completed with the average number of Ms delivered per visit (M-Score) using descriptive statistics and a generalized linear mixed-effects model. RESULTS: Over 70% of 2783 providers completed at least one education module. Rates of 4Ms care delivery were 1.37 (1.36-1.39, p < 0.001) times higher among those that completed an orientation course compared to those that did not. Higher uptake of education exhibited a dose-response relationship with rate ratios between 1.77 (1.74-1.80, p < 0.001) for 1-2 modules beyond orientation, up to 2.94 (2.90-2.99, p < 0.001) for eight or more modules. CONCLUSIONS: The self-directed learning environment (e.g., providers self-select the number and type of courses) reflects real-world variation in engagement. Despite this variation, significant improvements in 4Ms delivery were observed at any level of educational exposure, underscoring the value of prioritizing education time with quality improvement initiatives.

BRCA status dictates Wnt responsiveness in epithelial ovarian cancer.

The association of BRCA1 and BRCA2 mutations with increased risk for developing epithelial ovarian cancer is well established. However, the observed clinical differences, particularly the improved therapy response and patient survival in BRCA2 mutant (BRCA2mt) patients are unexplained. Our objective is to identify molecular pathways that are differentially regulated upon the loss of BRCA1 and BRCA2 function in ovarian cancer. Transcriptomic and pathway analysis comparing BRCA1 mutant (BRCA1mt), BRCA2mt and homologous recombination wild-type (HRwt) ovarian tumors showed differential regulation of the Wnt/ß-catenin pathway. Using Wnt3A-treated BRCA1/2 wild-type (BRCAwt), BRCA1null and BRCA2null mouse ovarian cancer cells, we observed preferential activation of the canonical Wnt/ß-catenin signaling in BRCAwt ovarian cancer cells while the non-canonical Wnt/ß-catenin signaling was preferentially activated in the BRCA1null cells. Interestingly, BRCA2null mouse ovarian cancer cells, demonstrated a unique response to Wnt3A with the preferential upregulation of the Wnt signaling inhibitor, Axin2. In addition, decreased phosphorylation and enhanced stability of ß-catenin were observed in BRCA2null mouse ovarian cancer cells, which correlated with increased inhibitory phosphorylation on GSK3ß. These findings open venues for the translation of these molecular observations into modalities that can impact patient survival.

Maintaining Survival While Improving Quality of Life: An Advanced Practitioner-Led Pilot Feasibility Study to Reduce Radiation Dose in Children With Brain Tumors.

Purpose: Oncology advanced practitioners (APs) are on the front line in treating adverse effects. Among children with brain tumors, treatments such as craniospinal irradiation (CSI) cause neurocognitive injury, endocrinopathies, and ototoxicity. High-dose CSI with concurrent chemotherapy allows high-risk embryonal tumors (non-anaplastic) good survival (70%), but significant distressing effects are commonly treated by APs in multidisciplinary long-term follow-up. The aim of this study was to test feasibility of reducing radiation dose with an AP-led protocol. Methods: An interdisciplinary team developed this pilot study with the primary outcome of fewer than two deaths in 10 patients (80% survival). Secondary outcomes were feasibility of an AP-led treatment protocol and acute/late effects of treatment. The AP held a pioneering role as principal investigator of a tumor treatment study. Exclusion criteria included age less than 3 years and anaplasia. The CSI was reduced from 36 to 24 Gy. All other treatment was standard. Results: Survival rate exceeded the primary outcome threshold (88%); the accrual rate (80%) and follow-up neurocognitive testing rate (75%) were acceptable. Eight children ages 3 to 19 years (M = 8) with tumors of varied molecular subtyping were enrolled. The single death occurred 2.5 years from diagnosis of multiorgan failure (without evidence of tumor). The mean survival is 11 years, with two college and one graduate degrees. Acute and late effects were decreased compared with the higher-dose CSI. Conclusion: APs who treat cancer adverse effects can also conduct clinical prospective studies to maintain survival rates and improve quality-of life-outcomes.

Iris melanoma in an Australian cohort.

BACKGROUND: To report the clinicopathological features and epidemiology of iris melanoma in Queensland, Australia. METHODS: This was a retrospective study of 86 patients with iris melanoma treated between 2001 and 2022 at the Queensland Ocular Oncology Service, Brisbane, Australia. Main outcome measures included demographics, clinical and phenotypic features, age-adjusted incidence and relative survival. RESULTS: Eighty-six patients (63% female) were included. Mean age was 54 years (range 17-82 years). The majority of patients (97%) were Caucasian, with blue eyes, fair skin and Fitzpatrick Skin Type I or II. Demographic features and clinical history showed a tendency for high ultraviolet radiation (UVR) exposure in the cohort. Histopathology was available in 69 cases (82%), and of these, 77% tumours were of spindle cell origin, with low-risk genetic profiles. Patients were followed for a mean of 8 years (median 7, range 1-21 years) after diagnosis, and only one case of metastasis was documented. CONCLUSIONS: The association of iris freckles, history of UVR exposure and dermatologic findings supports the role of UVR in iris melanoma. Occupation and avocation history, as well as evaluation of iris freckles may offer an easily accessible way of stratifying the risk of an individual for development of UVR-related uveal melanoma.

Pathological and clinical outcomes following neoadjuvant dual HER2 therapy for early-stage breast cancer: An Australian institutional real-world experience.

AIM: There has been significant progress made in developing novel targeted therapies in the neoadjuvant setting for non-metastatic HER2-positive breast cancer, which may be used in combination with conventional chemotherapy to optimise pathological responses at surgery. However, these therapies, particularly the chemotherapeutic components, may portend significant and long-lasting toxicity. Hence, de-escalation of treatment intensity has been an area of interest and was evaluated in the phase II NeoSphere study. Herein, we report the real-world pathological and survival outcomes from neoadjuvant taxane and dual HER2 blockade recorded at our centre. METHODS: This was a retrospective cohort study of patients receiving neoadjuvant pertuzumab, trastuzumab and taxane chemotherapy for non-metastatic HER2-positive breast cancer at a single centre in Sydney, Australia. We collected data pertaining to baseline demographic characteristics, pathological response rates, post-surgical prescribing patterns and also undertook survival analyses for invasive disease-free survival (iDFS) as well as exploratory analyses for correlations between pre-specified clinicopathologic factors and pathological response at surgery. RESULTS: Our population was largely similar at baseline to the NeoSphere study. 71 patients were included in the final analysis. 61% achieved a pathological complete response (pCR). Three patients received conventional chemotherapy in the adjuvant setting. 92% of included patients were alive and disease-free at 3 years of follow-up. Only 3 events of recurrence or death were recorded at a median follow-up of 32 months. No significant difference in iDFS was noted between patients achieving pCR and those with residual disease at surgery. CONCLUSION: This study demonstrates that de-escalated adjuvant treatment for HER2-positive early breast cancer achieved favourable pathological and long-term outcomes comparable to large trials, some utilising more intensive chemotherapeutic components.

Excess prevalence of preexisting chronic conditions in older adults with incident epilepsy.

OBJECTIVE: Prior studies have examined chronic conditions in older adults with prevalent epilepsy, but rarely among those with incident epilepsy. Identifying the chronic conditions with which older adults present at epilepsy incidence assists with the evaluation of disease burden in this patient population and informs coordinated care development. The aim of this study was to identify preexisting chronic conditions with excess prevalence in older adults with incident epilepsy compared to those without. METHODS: Using a random sample of 4 999 999 fee-for-service Medicare beneficiaries aged >65 years, we conducted a retrospective cohort study of epilepsy incidence in 2019. Non-Hispanic Black and Hispanic beneficiaries were oversampled. We identified preexisting chronic conditions from the 2016-2018 Medicare Beneficiary Summary Files and compared chronic condition prevalence between Medicare beneficiaries with and without incident epilepsy in 2019. We characterized variations in preexisting excess chronic condition prevalence by age, sex, and race/ethnicity, adjusting for the racial/ethnic oversampling. RESULTS: We observed excess prevalence of most preexisting chronic conditions in beneficiaries with incident epilepsy (n = 20 545, weighted n = 19 631). For stroke, for example, the adjusted prevalence rate ratio (APRR) was 4.82 (99% CI:4.60, 5.04), meaning that, compared to those without epilepsy, beneficiaries with incident epilepsy in 2019 had 4.82 times the stroke prevalence. Similarly, beneficiaries with incident epilepsy had a higher prevalence rate for preexisting neurological conditions (APRR = 3.17, 99% CI = 3.08-3.27), substance use disorders (APRR = 3.00, 99% CI = 2.81-3.19), and psychiatric disorders (APRR = 1.98, 99% CI = 1.94-2.01). For most documented chronic conditions, excess prevalence among beneficiaries with incident epilepsy in 2019 was larger for younger age groups compared to older age groups, and for Hispanic beneficiaries compared to both non-Hispanic White and non-Hispanic Black beneficiaries. SIGNIFICANCE: Compared to epilepsy-free Medicare beneficiaries, those with incident epilepsy in 2019 had a higher prevalence of most preexisting chronic conditions. Our findings highlight the importance of health promotion and prevention, multidisciplinary care, and elucidating shared pathophysiology to identify opportunities for prevention.

Efficacy and safety of single-dose artesunate plus sulfalene/pyrimethamine combined with praziquantel for the treatment of children with Schistosoma mansoni or Schistosoma haematobium in western Kenya: a randomised, open-label controlled trial.

BACKGROUND: Reliance on praziquantel for the treatment and control of schistosomiasis is likely to facilitate the emergence of drug resistance. Combination therapy targeting adult and juvenile schistosome worms is urgently needed to improve praziquantel efficacy and delay the potential development of drug resistance. We assessed the efficacy and safety of single-dose praziquantel combined with single-dose artesunate plus sulfalene-pyrimethamine in the treatment of Kenyan children with schistosomiasis. METHODS: This was an open-label, randomised clinical trial involving 426 school-aged children (7-15 years old) diagnosed with Schistosoma mansoni (by Kato-Katz) or S. haematobium (by urine filtration). They were randomly assigned (1:1:1) to receive a single dose of praziquantel (40 mg/kg), a single dose of artesunate plus sulfalene-pyrimethamine (12 mg/kg artesunate) or combination therapy using a single dose of praziquantel (40 mg/kg) combined with a single dose of artesunate plus sulfalene-pyrimethamine (12 mg/kg artesunate). The primary outcome was cure and egg reduction rates at 6 weeks post-treatment in the available case population. Adverse events were assessed within 3 h after treatment. RESULTS: Of the 426 children enrolled, 135 received praziquantel, 150 received artesunate plus sulfalene-pyrimethamine, and 141 received combination therapy. Outcome data were available for 348 (81.7%) children. For S. mansoni-infected children (n = 335), the cure rates were 75.6%, 60.7%, and 77.8%, and the egg reduction rates were 80.1%, 85.0%, and 88.4% for praziquantel, artesunate plus sulfalene-pyrimethamine, and combination therapy, respectively. For S. haematobium-infected children (n = 145), the corresponding cure rates were 81.4%, 71.1%, and 82.2%, and the egg reduction rates were 95.6%, 97.1%, and 97.7%, respectively. Seventy-one (16.7%) children reported mild-intensity adverse events. The drugs were well tolerated and no serious adverse events were reported. CONCLUSIONS: A single oral dose of praziquantel combined with artesunate plus sulfalene-pyrimethamine cured a high proportion of children with S. haematobium but did not significantly improve the treatment efficacy for either urinary or intestinal schistosomiasis. Sequential administration of praziquantel and artesunate plus sulfalene-pyrimethamine may enhance the efficacy and safety outcomes.

3D Nanocrystallography and the Imperfect Molecular Lattice.

Crystallographic analysis relies on the scattering of quanta from arrays of atoms that populate a repeating lattice. While large crystals built of lattices that appear ideal are sought after by crystallographers, imperfections are the norm for molecular crystals. Additionally, advanced X-ray and electron diffraction techniques, used for crystallography, have opened the possibility of interrogating micro- and nanoscale crystals, with edges only millions or even thousands of molecules long. These crystals exist in a size regime that approximates the lower bounds for traditional models of crystal nonuniformity and imperfection. Accordingly, data generated by diffraction from both X-rays and electrons show increased complexity and are more challenging to conventionally model. New approaches in serial crystallography and spatially resolved electron diffraction mapping are changing this paradigm by better accounting for variability within and between crystals. The intersection of these methods presents an opportunity for a more comprehensive understanding of the structure and properties of nanocrystalline materials.

An Analysis of the Association of Arrival Hemoglobin With Overtransfusion at 24 Hours in a Trauma Population.

BACKGROUND: Hemorrhage control and resuscitative concepts have evolved in recent years, leading to aggressive use of blood products in trauma patients. There is subsequently a potential risk for overtransfusion, adverse effects, and waste associated with unnecessary transfusion. Methods for conserving blood products are of particular importance in future large-scale combat operations where supply chains are likely to be strained. This study examined the association of emergency department (ED) arrival hemoglobin (HGB) with overtransfusion among survivors at 24 hours after major trauma at a military trauma center. MATERIALS AND METHODS: We performed a retrospective cohort study of patients who had a "major trauma" activation and received any red blood cells. Overtransfusion was defined as a HGB level ≥11.0 g/dL at 24 hours (outcome variable). Multivariable logistic regression statistics were used to compare groups and adjust for confounders (injury severity score, arrival modified shock index, injury type, age, and gender). A receiver operating characteristic was constructed with overtransfusion at 24 hours as the outcome (binary) and arrival HGB (continuous) as the independent variable. RESULTS: A total of 382 patients met inclusion criteria. Overtransfusion occurred in 30.4% (n = 116) of patients, with mean ED HGB levels of 13.2 g/dL (12.9 to 13.6) versus 11.6 g/dL (11.3 to 11.8, P < .001). Receiver operating characteristic analysis showed that ED HGB was highly sensitive (0.931) for predicting 24-hour overtransfusion. In our multivariable logistic regression analysis, when adjusting for injury severity score, arrival modified shock index, injury type, age, and gender, we found that the ED HGB value had a per-unit odds ratio of 1.60 (95% CI, 1.38 to 1.86) for 24-hour overtransfusion. Hospital and intensive care unit length of stay, mechanical ventilator days, and mortality did not increase. CONCLUSION: We found that the arrival HGB value was associated with overtransfusion among 24-hour survivors in a civilian trauma setting. Our findings will inform future prospective studies that investigate blood sparing clinical practice guidelines.

Maternal investment evolves with larger body size and higher diversification rate in sharks and rays.

Across vertebrates, live bearing evolved at least 150 times from ancestral egg laying into diverse forms and degrees of prepartum maternal investment.1,2 A key question is how reproductive diversity arose and whether reproductive diversification underlies species diversification.3,4,5,6,7,8,9,10,11 To test this, we evaluate the most basal jawed vertebrates: the sharks, rays, and chimaeras, which have one of the greatest ranges of reproductive and ecological diversity among vertebrates.2,12 We reconstruct the sequence of reproductive mode evolution across a phylogeny of 610 chondrichthyans.13 We reveal egg laying as ancestral, with live bearing evolving at least seven times. Matrotrophy evolved at least 15 times, with evidence of one reversal. In sharks, transitions to live bearing and matrotrophy are more prevalent in larger-bodied tropical species. Further, the evolution of live bearing is associated with a near doubling of the diversification rate, but there is only a small increase associated with the appearance of matrotrophy. Although pre-copulatory sexual selection is associated with increased rates of speciation in teleosts,3 sexual size dimorphism in chondrichthyans does not appear to be related to sexual selection,14,15 and instead we find increased rates of speciation associated with the colonization of novel habitats. This highlights a potential key difference between chondrichthyans and other fishes, specifically a slower rate of evolution of reproductive isolation following speciation, suggesting different rate-limiting mechanisms for diversification between these clades.16 The chondrichthyan diversification and radiation, particularly throughout shallow tropical shelf seas and oceanic pelagic habitats, appear to be associated with the evolution of live bearing and proliferation of a wide range of maternal investment in developing offspring.

Medication Adherence of Older Adults with Hypertension: A Systematic Review.

Objective: Hypertension (HTN) significantly increases the risk of stroke and heart disease, which are the leading causes of death and disability globally, particularly among older adults. Antihypertensive medication is a proven treatment for blood pressure control and preventing complications. However, medication adherence rates in older adults with HTN are low. In this review, we systematically identified factors influencing medication adherence in older adults with HTN. Methods: We applied the PRISMA guidelines and conducted systematic searches on PubMed, MEDLINE, and Google Scholar in July 2022 to identify preliminary studies reporting factors influencing medication adherence among older adults with HTN. The convergent integrated analysis framework suggested by the Joanna Briggs Institute for systematic reviews was adopted for data synthesis. Results: Initially, 448 articles were identified, and after title and abstract screening, 16 articles qualified for full-text review. During this phase, three articles were excluded for reporting on irrelevant populations or focusing on issues beyond the review's aim, leaving thirteen studies in the final review. After data synthesis, fifteen themes were extracted from the key findings of the included studies. The most prevalent themes included the number of medications used (53.9%, n=7 studies), financial status (38.5%, n=5), sex (38.5%, n=5), age (30.1%, n=4), duration of disease (23.1%, n=3), comorbidities (23.1%, n=3), and health compliance (23.1%, n=3). Other themes, such as education, health literacy, health belief, medication belief, perception of illness, patient-physician relationship, self-efficacy, and social support, were also identified. Conclusion: The findings of this review highlight critical areas for developing innovative, evidence-based programs to improve medication adherence in hypertensive older adults. Insights from this review can contribute to improving medication adherence and preventing future health complications.

Rapid P-TEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy.

Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. P-TEFb-mediated pause-release of RNA polymerase II (Pol II) is a conserved regulatory mechanism for synchronous transcriptional induction in response to heat shock, but this pro-survival role has not been examined in the applied context of cancer therapy. Using model systems of pediatric high-grade glioma, we show that rapid genome-wide reorganization of active chromatin facilitates P-TEFb-mediated nascent transcriptional induction within hours of exposure to therapeutic ionizing radiation. Concurrent inhibition of P-TEFb disrupts this chromatin reorganization and blunts transcriptional induction, abrogating key adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival. These studies reveal a central role for P-TEFb underpinning the early adaptive response to radiotherapy, opening avenues for combinatorial treatment in these lethal malignancies.

Pediatric Chordoma: A Tale of Two Genomes.

Little is known regarding the genomic alterations in chordoma, with the exception of loss of SMARCB1, a core member of the SWI/SNF complex, in poorly differentiated chordomas. A TBXT duplication and rs2305089 polymorphism, located at 6q27, are known genetic susceptibility loci. A comprehensive genomic analysis of the nuclear and mitochondrial genomes in pediatric chordoma has not yet been reported. In this study, we performed whole exome and mitochondrial DNA (mtDNA) genome sequencing on 29 chordomas from 23 pediatric patients. Findings were compared with that from whole genome sequencing datasets of 80 adult skull base chordoma patients. In the pediatric chordoma cohort, 81% percent of the somatic mtDNA mutations were observed in NADH complex genes, which is significantly enriched compared to the rest of the mtDNA genes (p=0.001). In adult chordomas, mtDNA mutations were also enriched in the NADH complex genes (p<0.0001). Furthermore, a progressive increase in heteroplasmy of non-synonymous mtDNA mutations was noted in patients with multiple tumors (p=0.0007). In the nuclear genome, rare likely germline in-frame indels in ARID1B, a member of the SWI/SNF complex located at 6q25.3, were observed in five pediatric patients (22%) and four patients in the adult cohort (5%). The frequency of rare ARID1B indels in the pediatric cohort is significantly higher than that of the adult cohort (p=0.0236, Fisher's exact test), but they were both significantly higher than that in the ethnicity-matched populations (p<5.9e-07 and p<0.0001174, respectively). Implications: germline ARID1B indels and mtDNA aberrations appear important for chordoma genesis, especially in pediatric chordoma.

The effects of HIV and oncogenic human papillomavirus on the tumor immune microenvironment of penile squamous cell carcinoma.

Penile squamous cell carcinoma (PSCC) occurs more frequently in some developing countries compared to developed countries. Infection with HIV and/or high-risk human papillomavirus (hrHPV) are risk factors for penile cancer development. The tumor microenvironment of PSCC may predict prognosis and may inform on the best targets for immunotherapy. We evaluated the immune microenvironment of penile tumors histologically, and determined whether and/or how HIV and/or hrHPV infections affect this tumor microenvironment. We conducted a prospective analytical cross-sectional study in which penile cancer tumors from 35 patients presenting at the University Teaching Hospital in Lusaka, Zambia were histologically staged and assessed for presence of tumor infiltrating immune cells and expression of immune checkpoints. Immunohistochemistry was used to evaluate immune checkpoints and infiltrating immune cells, while multiplex real-time polymerase chain reaction was used for hrHPV genotyping. The median age of all participants was 55 years. About 24% had advanced histological stage, 83% were HIV+, and 63% had hrHPV detected in their tumors using multiplex real-time polymerase chain reaction. PDL1 expression was significantly higher in HIV- participants than HIV+ participants (p = 0.02). Tumors with multiple hrHPV infections had a significantly higher number of cells expressing TIM3 than those with one hrHPV (p = 0.04). High grade tumors had a significantly higher infiltrate of FoxP3+ cells (p = 0.02), CD68+ cells (p = 0.01), CD163+ cells (p = 0.01), LAG3+ cells (p = 0.01), PD1+ cells (p = 0.01) and TIM3+ cells (p = 0.03) when compared with low grade tumours. There was significant moderate to strong positive correlation of cells expressing PD1 and LAG3 (⍴ = 0.69; p = 0.0001), PD1 and TIM3 (⍴ = 0.49; p = 0.017) and TIM3 and LAG3 PDL1 (⍴ = 0.61; p = 0.001). In conclusion, the tumor microenvironment of penile squamous cell carcinoma seems to be affected by both HIV and HPV infections. TIM3 appears to be a potential therapeutic target in PSCC patients with hrHPV infections.

Space wandering in the rodent default mode network.

The default mode network (DMN) is a large-scale brain network known to be suppressed during a wide range of cognitive tasks. However, our comprehension of its role in naturalistic and unconstrained behaviors has remained elusive because most research on the DMN has been conducted within the restrictive confines of MRI scanners. Here, we use multisite GCaMP (a genetically encoded calcium indicator) fiber photometry with simultaneous videography to probe DMN function in awake, freely exploring rats. We examined neural dynamics in three core DMN nodes-the retrosplenial cortex, cingulate cortex, and prelimbic cortex-as well as the anterior insula node of the salience network, and their association with the rats' spatial exploration behaviors. We found that DMN nodes displayed a hierarchical functional organization during spatial exploration, characterized by stronger coupling with each other than with the anterior insula. Crucially, these DMN nodes encoded the kinematics of spatial exploration, including linear and angular velocity. Additionally, we identified latent brain states that encoded distinct patterns of time-varying exploration behaviors and found that higher linear velocity was associated with enhanced DMN activity, heightened synchronization among DMN nodes, and increased anticorrelation between the DMN and anterior insula. Our findings highlight the involvement of the DMN in collectively and dynamically encoding spatial exploration in a real-world setting. Our findings challenge the notion that the DMN is primarily a "task-negative" network disengaged from the external world. By illuminating the DMN's role in naturalistic behaviors, our study underscores the importance of investigating brain network function in ecologically valid contexts.

Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease: The DIAN-TU-001 Randomized Clinical Trial.

Importance: Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective: To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, Setting, and Participants: From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions: In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main Outcomes and Measures: Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3-like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results: Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] ß = -242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] ß = -0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] ß = -0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] ß = -0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] ß = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] ß = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] ß = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and Relevance: This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. Trial Registration: ClinicalTrials.gov Identifier: NCT04623242.