Moiré Exchange Effect in Twisted WSe_{2}/WS_{2} Heterobilayer.

Moiré superlattices of layered transition metal dichalcogenides are proven to host periodic electron crystals due to strong correlation effects. These electron crystals can also be intertwined with intricate magnetic phenomena. In this Letter, we present our findings on the moiré exchange effect, resulting from the modulation of local magnetic moments by electron crystals within well-aligned WSe_{2}/WS_{2} heterobilayers. Employing polarization-resolved magneto-optical spectroscopy, we unveil a high-energy excitonic resonance near one hole per moiré unit cell (v=-1), which possesses a giant g factor several times greater than the already very large g factor of the WSe_{2} A exciton in this heterostructure. Supported by continuum model calculations, these high-energy states are found to be dark excitons brightened through Umklapp scattering from the moiré mini-Brillouin zone. When the carriers form a Mott insulating state near v=-1, the Coulomb exchange between doped carriers and excitons forms an effective magnetic field with moiré periodicity. This moiré exchange effect gives rise to the observed giant g factor for the excitonic Umklapp state.

Syllable processing is organized in discrete subregions of the human superior temporal gyrus.

Modular organization at approximately 1 mm scale could be fundamental to cortical processing, but its presence in human association cortex is unknown. Using custom-built, high-density electrode arrays placed on the cortical surface of 7 patients undergoing awake craniotomy for tumor excision, we investigated receptive speech processing in the left (dominant) human posterior superior temporal gyrus. Responses to consonant-vowel syllables and noise-vocoded controls recorded with 1,024 channel micro-grids at 200 µm pitch demonstrated roughly circular domains approximately 1.7 mm in diameter, with sharp boundaries observed in 128 channel linear arrays at 50 µm pitch, possibly consistent with a columnar organization. Peak latencies to syllables in different modules were bimodally distributed centered at 252 and 386 ms. Adjacent modules were sharply delineated from each other by their distinct time courses and stimulus selectivity. We suggest that receptive language cortex may be organized in discrete processing modules.

Network-wide risk convergence in gene co-expression identifies reproducible genetic hubs of schizophrenia risk.

The omnigenic model posits that genetic risk for traits with complex heritability involves cumulative effects of peripheral genes on mechanistic "core genes," suggesting that in a network of genes, those closer to clusters including core genes should have higher GWAS signals. In gene co-expression networks, we confirmed that GWAS signals accumulate in genes more connected to risk-enriched gene clusters, highlighting across-network risk convergence. This was strongest in adult psychiatric disorders, especially schizophrenia (SCZ), spanning 70% of network genes, suggestive of super-polygenic architecture. In snRNA-seq cell type networks, SCZ risk convergence was strongest in L2/L3 excitatory neurons. We prioritized genes most connected to SCZ-GWAS genes, which showed robust association to a CRISPRa measure of PGC3 regulation and were consistently identified across several brain regions. Several genes, including dopamine-associated ones, were prioritized specifically in the striatum. This strategy thus retrieves current drug targets and can be used to prioritize other potential drug targets.

Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe ulcerative colitis (PREDICT-UC): an open-label, multicentre, randomised controlled trial.

BACKGROUND: The optimal dosing strategy for infliximab in steroid-refractory acute severe ulcerative colitis (ASUC) is unknown. We compared intensified and standard dose infliximab rescue strategies and explored maintenance therapies following infliximab induction in ASUC. METHODS: In this open-label, multicentre, randomised controlled trial, patients aged 18 years or older from 13 Australian tertiary hospitals with intravenous steroid-refractory ASUC were randomly assigned (1:2) to receive a first dose of 10 mg/kg infliximab or 5 mg/kg infliximab (randomisation 1). Block randomisation was used and stratified by history of thiopurine exposure and study site, with allocation concealment maintained via computer-generated randomisation. Patients in the 10 mg/kg group (intensified induction strategy [IIS]) received a second dose at day 7 or earlier at the time of non-response; all patients in the 5 mg/kg group were re-randomised between day 3 and day 7 (1:1; randomisation 2) to a standard induction strategy (SIS) or accelerated induction strategy (AIS), resulting in three induction groups. Patients in the SIS group received 5 mg/kg infliximab at weeks 0, 2, and 6, with an extra 5 mg/kg dose between day 3 and day 7 if no response. Patients in the AIS group received 5 mg/kg infliximab at weeks 0, 1, and 3, with the week 1 dose increased to 10 mg/kg and given between day 3 and day 7 if no response. The primary outcome was clinical response by day 7 (reduction in Lichtiger score to <10 with a decrease of ≥3 points from baseline, improvement in rectal bleeding, and decreased stool frequency to ≤4 per day). Secondary endpoints assessed outcomes to day 7 and exploratory outcomes compared induction regimens until month 3. From month 3, maintenance therapy was selected based on treatment experience, with use of thiopurine monotherapy, combination infliximab and thiopurine, or infliximab monotherapy, with follow-up as a cohort study up to month 12. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02770040, and is completed. FINDINGS: Between July 20, 2016, and Sept 24, 2021, 138 patients were randomly assigned (63 [46%] female and 75 [54%] male); 46 received a first dose of 10 mg/kg infliximab and 92 received 5 mg/kg infliximab. After randomisation 1, we observed no significant difference in the proportion of patients who had a clinical response by day 7 between the 10 mg/kg and 5 mg/kg groups (30 [65%] of 46 vs 56 [61%] of 92, p=0·62; risk ratio adjusted for thiopurine treatment history, 1·06 [95% CI 0·94-1·20], p=0·32). We found no significant differences in secondary endpoints including time to clinical response or change in Lichtiger score from baseline to day 7. Two patients who received 10 mg/kg infliximab underwent colectomy in the first 7 days compared with no patients in the 5 mg/kg group (p=0·21). Three serious adverse events occurred in three patients in both the 10 mg/kg group and 5 mg/kg group. After randomisation 2, the proportions of patients with clinical response at day 14 (34 [74%] of 46 in the IIS group, 35 [73%] of 48 in the AIS group, and 30 [68%] of 44 in the SIS group, p=0·81), clinical remission at month 3 (23 [50%], 25 [52%], 21 [48%], p=0·92), steroid-free remission at month 3 (19 [41%], 20 [42%], 18 [41%], p=1·0), endoscopic remission at month 3 (21 [46%], 22 [46%], 21 [48%], p=0·98), and colectomy at month 3 (three [7%] of 45, nine [19%] of 47, five [12%] of 43, p=0·20) were not significantly different between groups. Between day 8 and month 3, the proportion of patients with at least one infectious adverse event possibly related to infliximab was two (4%) of 46 in the IIS group, eight (17%) of 48 in the AIS group, and eight (18%) of 44 in the SIS group (p=0·082). No deaths occurred in the study. INTERPRETATION: Infliximab is a safe and effective rescue therapy in ASUC. In steroid-refractory ASUC, a first dose of 10 mg/kg infliximab was not superior to 5 mg/kg infliximab in achieving clinical response by day 7. Intensified, accelerated, and standard induction regimens did not result in a significant difference in clinical response by day 14 or in remission or colectomy rates by month 3. FUNDING: Australian National Health and Medical Research Council, Gastroenterology Society of Australia, Gandel Philanthropy, Australian Postgraduate Award, Janssen-Cilag.

Transorbital approach clipping of middle cerebral artery aneurysm: a virtual reality morphometric anatomic study.

BACKGROUND: The transorbital approach (TOA) has a unique advantage to the more common lateral approaches as it provides direct access to the anterior middle fossa and medial sylvian fissure (SF) without significant dissection or retraction. However, when to use the TOA for surgical treatment of MCA aneurysms remains unclear. OBJECTIVE: This study details the feasibility of clipping unruptured middle cerebral artery (MCA) aneurysms via the TOA by highlighting the anatomic features that either facilitate or hinder the approach. METHODS: Virtual reality (VR) models of 25 MCA aneurysms from CT angiograms of actual patients were rendered with the relevant anatomic structures, including the neighboring temporal lobe and SF. TOA was performed on the models in VR and the globe was translated medially and inferiorly, replicating retraction used intraoperatively. Anatomic data, including the area of surgical freedom (AOF) at the aneurysm, were recorded. Trials of aneurysm clipping were conducted in VR and each aneurysm was classified as "possible" or "impossible" candidates for clipping via TOA. Separately, the relationship between surgical view and SF visualized was analyzed. RESULTS: Sixteen aneurysms were eliminated as candidates for TOA treatment either through VR clip trial and/or because the SF was inaccessible. The remaining 9 (36%) were candidates for TOA. Comparing the details of these two aneurysm categories with Mann Whitney U tests, there was a statistically significant difference in the AOF of the TOA approach and the width of the aneurysm dome. A clinical case report is also provided highlighting the VR rehearsal similarity with surgery. CONCLUSIONS: Given the minimally-invasive, technically-challenging approach, the feasibility and safety of TOA for MCA aneurysms must be evaluated before wide clinical adoption. This study identified AOF, aneurysm width, and SF accessibility as three features that may significantly impact the possibility of clipping MCA aneurysms via TOA.

Pan-cancer genomic analysis reveals FOXA1 amplification is associated with adverse outcomes in non-small cell lung, prostate, and breast cancers.

INTRODUCTION: Alterations in forkhead box A1 (FOXA1), a pioneer transcription factor, are associated with poor prognosis in breast cancer (BC) and prostate cancer (PC). We characterized FOXA1 genomic alterations and their clinical impacts in a large pan-cancer cohort from the AACR GENIE database. METHODS: FOXA1 alterations were characterized across >87,000 samples from >30 cancer types for primary and metastatic tumors alongside patient characteristics and clinical outcomes. FOXA1 alterations were queried in the MSK-MET cohort (a GENIE subset), allowing definition of hazard ratios (HRs) and survival estimates based on Cox proportional hazard models. RESULTS: FOXA1 was altered in 1,869 samples (2.1%), with distinct patterns across different cancers: PC enriched with indel-inframe alterations, BC with missense mutations, and lung cancers with copy number (CN) amplifications.Of 74,715 samples with FOXA1 CN profiles, amplification was detected in 834 (1.1%). Amplification was most common in non-small cell lung cancer (NSCLC, 3% in primary; 6% in metastatic) and small cell lung cancer (4.1% primary; 3.5% metastatic), followed by BC (2% primary; 1.6% metastatic) and PC (2.2% primary; 1.6% metastatic).CN amplifications were associated with decreased overall survival in NSCLC (HR: 1.45, 95%CI: 1.06-1.99, p = .02), BC (HR: 3.04, 95%CI: 1.89-4.89, p = 4e-6), and PC (HR: 1.94, 95%CI: 1.03-3.68, p = .04). Amplifications were associated with wide-spread metastases in NSCLC, BC, and PC. CONCLUSIONS: FOXA1 demonstrates distinct alteration profiles across cancer sites. Our findings suggest an association between FOXA1 amplification and both enhanced metastatic potential and decreased survival, highlighting prognostic and therapeutic potential in breast cancer, prostate cancer, and NSCLC.

Spatial Variability in Relationships between Early Childhood Lead Exposure and Standardized Test Scores in Fourth Grade North Carolina Public School Students (2013-2016).

BACKGROUND: Exposure to lead during childhood is detrimental to children's health. The extent to which the association between lead exposure and elementary school academic outcomes varies across geography is not known. OBJECTIVE: Estimate associations between blood lead levels (BLLs) and fourth grade standardized test scores in reading and mathematics in North Carolina using models that allow associations between BLL and test scores to vary spatially across communities. METHODS: We link geocoded, individual-level, standardized test score data for North Carolina public school students in fourth grade (2013-2016) with detailed birth records and blood lead testing data retrieved from the North Carolina childhood blood lead state registry on samples typically collected at 1-6 y of age. BLLs were categorized as: 1µg/dL (reference), 2µg/dL, 3-4µg/dL and ≥5µg/dL. We then fit spatially varying coefficient models that incorporate information sharing (smoothness), across neighboring communities via a Gaussian Markov random field to provide a global estimate of the association between BLL and test scores, as well as census tract-specific estimates (i.e., spatial coefficients). Models adjusted for maternal- and child-level covariates and were fit separately for reading and math. RESULTS: The average BLL across the 91,706 individuals in the analysis dataset was 2.84µg/dL. Individuals were distributed across 2,002 (out of 2,195) census tracts in North Carolina. In models adjusting for child sex, birth weight percentile for gestational age, and Medicaid participation as well as maternal race/ethnicity, educational attainment, marital status, and tobacco use, BLLs of 2µg/dL, 3-4µg/dL and ≥5µg/dL were associated with overall lower reading test scores of -0.28 [95% confidence interval (CI): -0.43, -0.12], -0.53 (-0.69, -0.38), and -0.79 (-0.99, -0.604), respectively. For BLLs of 1µg/dL, 2µg/dL, 3-4µg/dL and ≥5µg/dL, spatial coefficients-that is, tract-specific adjustments in reading test score relative to the "global" coefficient-ranged from -9.70 to 2.52, -3.19 to 3.90, -11.14 to 7.85, and -4.73 to 4.33, respectively. Results for mathematics were similar to those for reading. CONCLUSION: The association between lead exposure and reading and mathematics test scores exhibits considerable heterogeneity across North Carolina communities. These results emphasize the need for prevention and mitigation efforts with respect to lead exposures everywhere, with special attention to locations where the cognitive impact is elevated. https://doi.org/10.1289/EHP13898.

Immunogenicity of mRNA vs. BBV152 vaccine boosters against Omicron subvariants: Final results from Phase B of the PRIBIVAC study, a randomized clinical trial.

BACKGROUND: BBV152 (Covaxin™) is a whole-virion inactivated SARS-CoV-2 vaccine mixed with an immune adjuvant. We aimed to compare immune responses after booster vaccination with heterologous BBV152 versus homologous mRNA vaccine. METHODS: We conducted a randomized, participant-blinded, controlled trial. Fifty mRNA-vaccinated participants were enrolled and randomized to receive an mRNA booster (n = 26) or BBV152 (n = 24). Blood samples were collected pre-vaccination, and at Day 7, 28, 180 and 360 post-booster for analysis of humoral and cellular immune responses. Primary end point was the SARS-CoV-2 anti-spike antibody titer at day 28. RESULTS: Recruitment began in January 2022 and was terminated early due to the BBV152 group meeting pre-specified criteria for futility. At Day 28 post-boost, mean SARS-CoV-2 spike antibody titers were lower with BBV152 (2004 IU/mL; 95 % confidence interval [CI], 1132-3548) vs mRNA (26,669 IU/mL; 95 % CI, 21,330-33,266; p < 0.0001), but comparable levels of spike-specific CD4 and cytotoxic T-cells were observed. Anti-spike antibody titers remained significantly different at Day 180: BBV152 4467 IU/mL (95 % CI, 1959-10,186) vs mRNA 20,749 IU/mL (95 % CI, 12,303-35,075; p = 0.0017). Levels of surrogate virus neutralizing antibodies against ancestral and Omicron subvariants BA.1 and BA.2 were significantly higher among mRNA recipients at Day 180, including after adjusting for intercurrent infection. By Day 360, anti-spike antibody titers and neutralizing antibody levels against Omicron subvariants became similar between vaccine groups. By the end of the study, 16 in each arm (mRNA 64 % and BBV152 69.6 %) had breakthrough infections and time to COVID-19 infection between vaccine groups were similar (p = 0.63). CONCLUSIONS: Wild-type SARS-CoV-2 anti-spike antibody titer and surrogate virus neutralizing test levels against wild-type SARS-CoV-2 and Omicron subvariants BA.1/BA.2/BA.5 were significantly higher at Day 28 and 180 in individuals who received booster vaccination with an mRNA vaccine compared with BBV152. CLINICAL TRIAL REGISTRATION NUMBER: NCT05142319.

Twelve-month outcomes of a community-based, father-daughter physical activity program delivered by trained facilitators.

BACKGROUND: Dads and Daughters Exercising and Empowered (DADEE) is a program targeting fathers/father-figures to improve their daughters' physical activity and well-being. Previous randomised controlled efficacy and effectiveness trials of DADEE demonstrated meaningful improvements in a range of holistic outcomes for both fathers and daughters in the short-term. This study aims to assess the long-term impact (12-months) of the program when delivered in the community by trained facilitators. METHODS: Fathers/father-figures and their primary school-aged daughters were recruited from Newcastle, Australia into a single-arm, non-randomised, pre-post study with assessments at baseline, 10-weeks (post-intervention) and 12-months. The 9-session program included weekly 90-min educational and practical sessions, plus home-based tasks. The primary outcome was fathers' and daughters' days per week meeting national physical activity recommendations (≥ 30 min/day of MVPA for fathers, ≥ 60 min/day MVPA for daughters). Secondary outcomes included physical activity, screen time, self-esteem, father-daughter relationship, social-emotional well-being, parenting measures, and process outcomes (including recruitment, attendance, retention and program acceptability). RESULTS: Twelve programs were delivered with 257 fathers (40.0 ± 9.2 years) and 285 daughters (7.7 ± 1.9 years). Mixed effects regression models revealed significant intervention effects for the primary outcome, with fathers increasing the days/week meeting physical activity recommendations by 27% at 10-weeks (p < 0.001) and by 19% at 12-months (p < 0.001) compared with baseline. Likewise, for daughters there was a significant increase by 25% at 10-weeks (p < 0.001) and by 14% at 12-months (p = 0.02) when compared to baseline. After conducting a sensitivity analysis with participants unaffected by COVID-19 lockdowns (n = 175 fathers, n = 192 daughters), the primary outcome results strengthened at both time-points for fathers and at 12-months for daughters. Additionally, the sensitivity analysis revealed significant intervention effects at post-program and 12-months for all secondary outcomes in both fathers and daughters. Furthermore, the process outcomes for recruitment capability, attendance, retention and satisfaction levels were high. CONCLUSIONS: Findings provide support for a sustained effect of the DADEE program while delivered in a community setting by trained facilitators. Further investigation is required to identify optimised implementation processes and contextual factors to deliver the program at scale. TRIAL REGISTRATION: ACTRN12617001450303 . Date registered: 12/10/2017.

Quantitative susceptibility and T1 ρ mapping of knee articular cartilage at 3T.

T1 ρ and Quantitative Susceptibility Mapping (QSM) are evolving as substrates for quantifying the progressive nature of knee osteoarthritis. Objective: To evaluate the effects of spin lock time combinations on depth-dependent T1 ρ estimation, in adjunct to QSM, and characterize the degree of shared variance in QSM and T1 ρ for the quantitative measurement of articular cartilage. Design: Twenty healthy participants (10 â€‹M/10F, 22.2 â€‹± â€‹3.4 years) underwent bilateral knee MRI using T1 ρ MAPPS sequences with varying TSLs ([0-120] ms), along with a 3D spoiled gradient echo for QSM. Five total TSL combinations were used for T1 ρ computation, and direct depth-based comparison. Depth-wide variance was assessed in comparison to QSM as a basis to assess for depth-specific variation in T1 ρ computations across healthy cartilage. Results: Longer T1 ρ relaxation times were observed for TSL combinations with higher spin lock times. Depth-specific differences were documented for both QSM and T1 ρ , with most change found at ∼60% depth of the cartilage, relative to the surface. Direct squared linear correlation revealed that most T1 ρ TSL combinations can explain over 30% of the variability in QSM, suggesting inherent shared sensitivity to cartilage microstructure. Conclusions: T1 ρ mapping is subjective to the spin lock time combinations used for computation of relaxation times. When paired with QSM, both similarities and differences in signal sensitivity may be complementary to capture depth-wide changes in articular cartilage.

Value of Engagement in Digital Health Technology Research: Evidence Across 6 Unique Cohort Studies.

BACKGROUND: Wearable digital health technologies and mobile apps (personal digital health technologies [DHTs]) hold great promise for transforming health research and care. However, engagement in personal DHT research is poor. OBJECTIVE: The objective of this paper is to describe how participant engagement techniques and different study designs affect participant adherence, retention, and overall engagement in research involving personal DHTs. METHODS: Quantitative and qualitative analysis of engagement factors are reported across 6 unique personal DHT research studies that adopted aspects of a participant-centric design. Study populations included (1) frontline health care workers; (2) a conception, pregnant, and postpartum population; (3) individuals with Crohn disease; (4) individuals with pancreatic cancer; (5) individuals with central nervous system tumors; and (6) families with a Li-Fraumeni syndrome affected member. All included studies involved the use of a study smartphone app that collected both daily and intermittent passive and active tasks, as well as using multiple wearable devices including smartwatches, smart rings, and smart scales. All studies included a variety of participant-centric engagement strategies centered on working with participants as co-designers and regular check-in phone calls to provide support over study participation. Overall retention, probability of staying in the study, and median adherence to study activities are reported. RESULTS: The median proportion of participants retained in the study across the 6 studies was 77.2% (IQR 72.6%-88%). The probability of staying in the study stayed above 80% for all studies during the first month of study participation and stayed above 50% for the entire active study period across all studies. Median adherence to study activities varied by study population. Severely ill cancer populations and postpartum mothers showed the lowest adherence to personal DHT research tasks, largely the result of physical, mental, and situational barriers. Except for the cancer and postpartum populations, median adherences for the Oura smart ring, Garmin, and Apple smartwatches were over 80% and 90%, respectively. Median adherence to the scheduled check-in calls was high across all but one cohort (50%, IQR 20%-75%: low-engagement cohort). Median adherence to study-related activities in this low-engagement cohort was lower than in all other included studies. CONCLUSIONS: Participant-centric engagement strategies aid in participant retention and maintain good adherence in some populations. Primary barriers to engagement were participant burden (task fatigue and inconvenience), physical, mental, and situational barriers (unable to complete tasks), and low perceived benefit (lack of understanding of the value of personal DHTs). More population-specific tailoring of personal DHT designs is needed so that these new tools can be perceived as personally valuable to the end user.

Motivators and barriers for studying podiatry in Australia and New Zealand: A mixed methods study.

BACKGROUND: Podiatry enrolments at Australian and New Zealand universities have decreased by 17.3% since 2015, which threatens the profession's sustainability and the health and wellbeing of Australian and New Zealand people and communities. Reasons for this decline remain unclear due to insufficient evidence on factors influencing career choices. The overarching aim of this study was to identify motivators and barriers for studying podiatry in Australia and New Zealand. METHODS: This study used a convergent mixed methods design. Students enrolled in (i) podiatry and (ii) relevant non-podiatry health, sport or science programs at nine Australian and one New Zealand university, were invited to participate in an online survey. First-year podiatry students were also invited to participate in an online workshop. Quantitative data were analysed using descriptive statistics and linear/logistic regression models. Three independent assessors used inductive thematic analysis for the qualitative data. RESULTS: Overall, 278 podiatry students (mean age 24.9 ± 8.5 years, 65.1% female) and 553 non-podiatry students (mean age 24.8 ± 8.2 years, 75.4% female; 32.2% from physiotherapy and 29.1% from occupational therapy) responded to the survey. Interest in a health-related career, wanting to make a difference to people's health, and opportunity to care for people from different backgrounds/age groups were key motivating factors among podiatry students. Barriers to studying podiatry were encountered by 28.1% of podiatry students. Thematic analysis identified seven themes concerning career choice, which are as follows: (i) awareness of profession and scope of practice; (ii) stereotypes and negative perceptions of the profession; (iii) awareness of career pathways; (iv) job prospects and earning potential; (v) working with people and building relationships; (vi) podiatry is not the first preference; and (vii) barriers which limit student enrolment. CONCLUSIONS: There are a variety of factors that motivate and influence students to study podiatry, however, altruistic reasons are most highly rated. Allied health students have limited understanding of the scope of practice and career opportunities in podiatry. Additionally, the podiatry profession often faces negative stereotypes. Further work is required to reverse the negative stereotypes and perceptions of podiatry and build knowledge of the profession's scope of practice, career pathways/opportunities, job prospects and earning potential.

A systematic review of focused ultrasound for psychiatric disorders: current applications, opportunities, and challenges.

OBJECTIVE: Advancements in MRI-guided focused ultrasound (MRgFUS) technology have led to the successful treatment of select movement disorders. Based on the comparative success between ablation and deep brain stimulation, interest arises in focused ultrasound (FUS) as a promising treatment modality for psychiatric illnesses. In this systematic review, the authors examined current applications of FUS for psychiatric conditions and explored its potential opportunities and challenges. METHODS: The authors performed a comprehensive review using the PRISMA guidelines of studies investigating psychiatric applications for FUS. Articles indexed on PubMed between 2014 to 2024 were included. The authors synthesized the psychiatric conditions treated, neural targets, outcomes, study design, and sonication parameters, and they reviewed important considerations for the treatment of psychiatric disorders with FUS. They also discussed active clinical trials in this research domain. RESULTS: Of 250 articles, 10 met the inclusion criteria. Eight articles investigated the clinical, safety, and imaging correlates of MRgFUS in obsessive-compulsive disorder (OCD), whereas 3 examined treatment-resistant depression. Bilateral anterior capsulotomy resulted in a full responder rate of 67% (≥ 35% reduction in the Yale-Brown Obsessive-Compulsive Scale score) and 33% (≥ 50% reduction in the score on the Hamilton Rating Scale for Depression) in OCD and treatment-resistant depression, respectively. Sonications ranged from 8 to 36 with targeted lesional temperatures of 51°C-56°C. Lesions in the anterodorsal aspect of the anterior limb of the internal capsule (ALIC) and increased functional connectivity to the left dorsolateral prefrontal cortex and dorsal anterior cingulate cortex significantly predicted reduction in symptoms among patients with OCD, with decreases in beta-band activity in the frontocentral and temporal regions associated with reductions in depression and anxiety. Treatment of the nucleus accumbens with low-intensity FUS (LIFU) in patients with opioid-use disorders resulted in significant reductions in cue-reactive cravings, lasting up to 90 days. No serious adverse events were reported, including cognitive decline. Side effects were generally mild and transient, consisting of headaches, pin-site swelling, and nausea. Fourteen active clinical trials were identified, primarily targeting depression with LIFU. CONCLUSIONS: Currently, FUS for psychiatric conditions is centered on OCD, with early pilot studies demonstrating promising safety and efficacy. Further research expanding on defining optimal patient selection, study design, intensity, and sonication parameters is warranted, particularly as FUS expands to other psychiatric illnesses and incorporates LIFU paradigms. Ethical considerations such as patient consent and equitable access also remain paramount.

It's all relative: A multi-generational study using ForenSeq™ Kintelligence.

The successful application of Forensic Investigative Genetic Genealogy (FIGG) to the identification of unidentified human remains and perpetrators of serious crime has led to a growing interest in its use internationally, including Australia. Routinely, FIGG has relied on the generation of high-density single nucleotide polymorphism (SNP) profiles from forensic samples using whole genome array (WGA) (∼650,000 or more SNPs) or whole genome sequencing (WGS) (millions of SNPs) for DNA segment-based comparisons in commercially available genealogy databases. To date, this approach has required DNA of a quality and quantity that is often not compatible with forensic samples. Furthermore, it requires the management of large data sets that include SNPs of medical relevance. The ForenSeq™ Kintelligence kit, comprising of 10,230 SNPs including 9867 for kinship association, was designed to overcome these challenges using a targeted amplicon sequencing-based method developed for low DNA inputs, inhibited and/or degraded forensic samples. To assess the ability of the ForenSeq™ Kintelligence workflow to correctly predict biological relationships, a comparative study comprising of 12 individuals from a family (with varying degrees of relatedness from 1st to 6th degree relatives) was undertaken using ForenSeq™ Kintelligence and a WGA approach using the Illumina Global Screening Array-24 version 3.0 Beadchip. All expected 1st, 2nd, 3rd, 4th and 5th degree relationships were correctly predicted using ForenSeq™ Kintelligence, while the expected 6th degree relationships were not detected. Given the (often) limited availability of forensic samples, findings from this study will assist Australian Law enforcement and other agencies considering the use of FIGG, to determine if the ForenSeq™ Kintelligence is suitable for existing workflows and casework sample types considered for FIGG.

Impact of the Graphic Memoir "My Degeneration: A Journey Through Parkinson's" on Patients With Parkinson's Disease: A Mixed Methods Study.

INTRODUCTION: Understanding the lived experience of illness is important for empowering patients and informing health care practitioners. This study investigated the impact of a book-length comic memoir, My Degeneration: A Journey Through Parkinson's, by Peter Dunlap-Shohl, on patients' mental health, knowledge, and attitudes about living with Parkinson's disease (PD). The authors further explored which patients found the book to be beneficial and why. METHODS: In this convergent mixed methods study, patients with PD were recruited from a multidisciplinary movement disorders clinic in 2019-2020 and were eligible if cognitively intact; English-speaking; had stage I, II, or III PD; and < 12 months had elapsed since diagnosis. Participants received My Degeneration to read at home, measures were obtained pre- and postintervention, and participants were interviewed within approximately 1 month. RESULTS: Thirty participants completed the study (13 males and 17 female; mean age = 59 years). Four qualitative themes emerged: Reading My Degeneration 1) validated the experience of living with PD, 2) reinforced practical behaviors that support well-being, 3) provided insight about the illness experience, and 4) was emotionally and physically taxing. There were no statistically significant pre-/postintervention changes in knowledge, self-efficacy, hope, or emotional distress. Book "endorsers" appreciated Dunlap-Shohl's dark humor and resonated with his experience; "detractors" found the book to be blunt and sometimes frightening. DISCUSSION/CONCLUSION: Participants who liked the book-the "endorsers"-revealed that it deeply resonated with them and helped them realize they were not alone with the disease. Many commented that Dunlap-Shohl's story was in some ways their story-and that this was both practically and emotionally reassuring. My Degeneration has the potential to benefit patients who appreciate comics, enjoy dark humor, and are not overly pessimistic.

Cardiovascular Risks and Outcomes Among Chinese American Immigrants: Insights From the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Immigrants experience changes in cardiovascular risk factors and racial disparities in both cardiovascular health prevention and outcomes upon immigration. We aimed to examine cardiovascular risk factors and outcomes among Chinese American immigrants enrolled in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort. METHODS AND RESULTS: We analyzed data from 746 Chinese American immigrants in the MESA study with a median follow-up period of 17.8 years. The mean age of the cohort was 62.3 years, with 52.7% being women. Kaplan-Meier curves and Cox proportional hazards models were used to assess the association of immigration history, geographic location, biomarkers, and cardiac imaging parameters with cardiovascular risk factors and cardiovascular outcomes. The Cox hazards models were adjusted for known family history of heart disease, education level, sex, diabetes, hypertension, age, and body mass index. Although immigration history categorized as earlier (<20 years) versus later (≥20 years) showed no association with cardiovascular outcomes, the duration of residence in the United States emerged as a strong predictor for an increased risk of cardiovascular disease death (hazard ratio 1.39 [95% CI, 1.07-1.8]; P=0.012). All-cause mortality differed significantly between the Chinese immigrants from Los Angeles and those from Chicago, with higher survival probability in Chicago (log-rank test, P=0.018). Furthermore, elevated levels of N-terminal pro-brain natriuretic peptide levels, left ventricular mass, and coronary artery calcium scores were associated with the risk of cardiovascular disease among Chinese immigrants. CONCLUSIONS: Within the MESA cohort, the duration of residence and geographic location were associated with the risk of cardiovascular disease outcomes among Chinese immigrants.

[(1,2,5,6-η)-Cyclo-octa-1,5-diene](1-ethyl-4-isobutyl-1,2,4-triazol-5-yl-idene)(tri-phenyl-phosphane)rhodium(I) tetra-fluorido-borate.

A new, cationic N-heterocyclic carbene RhI complex with a tetra-fluorido-borate counter-anion, [Rh(C8H12)(C8H15N3)(C18H15P)]BF4, has been synthesized and structurally characterized. There are two independent ion pairs in the asymmetric unit. Each complex cation exhibits a distorted square-planar conformation around the RhI atom. Bond lengths and bond angles are as expected for an Rh-NHC complex. There are several close, non-standard C-H⋯F hydrogen-bonding inter-actions between the ions. One of the tetra-fluorido-borate anions shows statistical disorder of the F atoms.

Relationships between soil test phosphorus and county-level agricultural surplus phosphorus.

National nutrient inventories provide surplus phosphorus (P) estimates derived from county-scale mass balance calculations using P inputs from manure and fertilizer sales and P outputs from crop yield data. Although bioavailable P and surplus P are often correlated at the field scale, few studies have investigated the relationship between measured soil P concentrations of large-scale soil testing programs and inventory-based surplus P estimates. In this study, we assessed the relationship between national surplus P data from the NuGIS dataset and laboratory-measured soil test phosphorus (STP) at the county scale for Arkansas, North Carolina, and Oklahoma. For optimal periods of surplus P aggregation, surplus P was positively correlated with STP based on both Pearson (Arkansas: r = 0.65, North Carolina: r = 0.45, Oklahoma: r = 0.52) and Spearman correlation coefficients (Arkansas: ρ = 0.57, North Carolina: ρ = 0.28, and Oklahoma: ρ = 0.66). Based on Pearson correlations, the optimal surplus P aggregation periods were 10, 30, and 4 years for AR, NC, and OK, respectively. On average, STP was more strongly correlated with surplus P than with individual P inventory components (fertilizer, manure, and crop removal), except in North Carolina. In Arkansas and North Carolina, manure P was positively correlated with STP, and fertilizer P was negatively correlated with STP. Altogether, results suggest that surplus P moderately correlates with STP concentrations, but aggregation period and location-specific factors influence the strength of the relationship.

H3K27M diffuse midline glioma is homologous recombination defective and sensitized to radiotherapy and NK cell-mediated antitumor immunity by PARP inhibition.

Background: Radiotherapy (RT) is the primary treatment for diffuse midline glioma (DMG), a lethal pediatric malignancy defined by histone H3 lysine 27-to-methionine (H3K27M) mutation. Based on the loss of H3K27 trimethylation producing broad epigenomic alterations, we hypothesized that H3K27M causes a functional double-strand break (DSB) repair defect that could be leveraged therapeutically with PARP inhibitor and RT for selective radiosensitization and antitumor immune responses. Methods: H3K27M isogenic DMG cells and orthotopic brainstem DMG tumors in immune deficient and syngeneic, immune competent mice were used to evaluate the efficacy and mechanisms of PARP1/2 inhibition by olaparib or PARP1 inhibition by AZD9574 with concurrent RT. Results: H3K27M mutation caused an HRR defect characterized by impaired RT-induced K63-linked polyubiquitination of histone H1 and inhibition of HRR protein recruitment. H3K27M DMG cells were selectively radiosensitized by olaparib in comparison to isogenic controls, and this effect translated to efficacy in H3K27M orthotopic brainstem tumors. Olaparib and RT induced an innate immune response and induction of NK cell (NKG2D) activating ligands leading to increased NK cell-mediated lysis of DMG tumor cells. In immunocompetent syngeneic orthotopic DMG tumors, either olaparib or AZD9574 in combination with RT enhanced intratumoral NK cell infiltration and activity in association with NK cell-mediated therapeutic responses and favorable activity of AZD9574. Conclusions: The HRR deficiency in H3K27M DMG can be therapeutically leveraged with PARP inhibitors to radiosensitize and induce an NK cell-mediated antitumor immune response selectively in H3K27M DMG, supporting the clinical investigation of best-in-class PARP inhibitors with RT in DMG patients. Key points: H3K27M DMG are HRR defective and selectively radiosensitized by PARP inhibitor.PARP inhibitor with RT enhances NKG2D ligand expression and NK cell-mediated lysis.NK cells are required for the therapeutic efficacy of PARP inhibitor and RT. Importance of the Study: Radiotherapy is the cornerstone of H3K27M-mutant diffuse midline glioma treatment, but almost all patients succumb to tumor recurrence with poor overall survival, underscoring the need for RT-based precision combination therapy. Here, we reveal HRR deficiency as an H3K27M-mediated vulnerability and identify a novel mechanism linking impaired RT-induced histone H1 polyubiquitination and the subsequent RNF168/BRCA1/RAD51 recruitment in H3K27M DMG. This model is supported by selective radiosensitization of H3K27M DMG by PARP inhibitor. Notably, the combination treatment results in NKG2D ligand expression that confers susceptibility to NK cell killing in H3K27M DMG. We also show that the novel brain penetrant, PARP1-selective inhibitor AZD9574 compares favorably to olaparib when combined with RT, prolonging survival in a syngeneic orthotopic model of H3K27M DMG. This study highlights the ability of PARP1 inhibition to radiosensitize and induce an NK cell-mediated antitumor immunity in H3K27M DMG and supports future clinical investigation.