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Deep brain stimulation (DBS) for Parkinson's disease (PD) is an established advanced therapy that produces therapeutic effects through high frequency stimulation. Although this therapeutic option leads to improved clinical outcomes, the mechanisms of the underlying efficacy of this treatment are not well understood. Therefore, investigation of DBS and its postoperative effects on brain architecture is of great interest. Diffusion weighted imaging (DWI) is an advanced imaging technique, which has the ability to estimate the structure of white matter fibers; however, clinical application of DWI after DBS implantation is challenging due to the strong susceptibility artifacts caused by implanted devices. This study aims to evaluate the feasibility of generating meaningful white matter reconstructions after DBS implantation; and to subsequently quantify the degree to which these tracts are affected by post-operative device-related artifacts.DWI was safely performed before and after implanting electrodes for DBS in 9 PD patients. Differences within each subject between pre- and post-implantation FA, MD, and RD values for 123 regions of interest (ROIs) were calculated. While differences were noted globally, they were larger in regions directly affected by the artifact. White matter tracts were generated from each ROI with probabilistic tractography, revealing significant differences in the reconstruction of several white matter structures after DBS. Tracts pertinent to PD, such as regions of the substantia nigra and nigrostriatal tracts, were largely unaffected.The aim of this study was to demonstrate the feasibility and clinical applicability of acquiring and processing DWI post-operatively in PD patients after DBS implantation. The presence of global differences provides an impetus for acquiring DWI shortly after implantation to establish a new baseline against which longitudinal changes in brain connectivity in DBS patients can be compared. Understanding that post-operative fiber tracking in patients is feasible on a clinically-relevant scale has significant implications for increasing our current understanding of the pathophysiology of movement disorders, and may provide insights into better defining the pathophysiology and therapeutic effects of DBS. Keywords: Postoperative imaging, Clinical feasibility, Deep brain stimulation, Diffusion weighted imaging, Tractography, Susceptibility artifact, Parkinson's disease

BackgroundHyperbaric oxygen (HBO2) treatment is used across a range of medical specialties for a variety of applications, particularly where hypoxia and inflammation are important contributors. Because of its hypoxia-relieving and anti-inflammatory effects HBO2 may be useful for new indications not currently approved by the Undersea and Hyperbaric Medical Society. Identifying these new applications for HBO2 is difficult because individual centers may only treat a few cases and not track the outcomes consistently. The web-based International Multicenter Registry for Hyperbaric Oxygen Therapy captures prospective outcome data for patients treated with HBO2 therapy. These data can then be used to identify new potential applications for HBO2, which has relevance for a range of medical specialties. ObjectiveAlthough hyperbaric medicine has established indications, new ones continue to emerge. One objective of this registry study was to identify cases where HBO2 has been used for conditions falling outside of current Undersea and Hyperbaric Medical Society–approved indications and present outcome data for them. MethodsThis descriptive study used data from a web-based, multicenter, international registry of patients treated with HBO2. Participating centers agree to collect data on all patients treated using standard outcome measures, and individual centers send deidentified data to the central registry. HBO2 treatment programs in the United States, the United Kingdom, and Australia participate. Demographic, outcome, complication, and treatment data, including pre- and posttreatment quality of life questionnaires (EQ-5D-5L) were collected for individuals referred for HBO2 treatment. ResultsOut of 9726 patient entries, 378 (3.89%) individuals were treated for 45 emerging indications. Post–COVID-19 condition (PCC; also known as postacute sequelae of COVID-19; 149/378, 39.4%), ulcerative colitis (47/378, 12.4%), and Crohn disease (40/378, 10.6%) accounted for 62.4% (n=236) of the total cases. Calciphylaxis (20/378, 5.3%), frostbite (18/378, 4.8%), and peripheral vascular disease–related wounds (12/378, 3.2%) accounted for a further 13.2% (n=50). Patients with PCC reported significant improvement on the Neurobehavioral Symptom Inventory (NSI score: pretreatment=30.6; posttreatment=14.4; P

Abstract Pancreatic acinar cell carcinoma (PACC) is a rare form of pancreatic cancer that commonly harbors targetable alterations, including activating fusions in the MAPK pathway and loss-of-function (LOF) alterations in DNA damage response/homologous recombination DNA repair-related genes. Here, we describe a patient with PACC harboring both somatic biallelic LOF of NBN and an activating NTRK1 fusion. Upon disease progression following 13 months of treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), genomic analysis of a metastatic liver biopsy revealed the emergence of a novel reversion mutation restoring the reading frame of NBN. To our knowledge, genomic reversion of NBN has not been previously reported as a resistance mechanism in any tumor type. The patient was treated with, but did not respond to, targeted treatment with a selective NTRK inhibitor. This case highlights the complex but highly actionable genomic landscape of PACC and underlines the value of genomic profiling of rare tumor types such as PACC.

To promote collaboration across canine science, address replicability issues, and advance open science practices within animal cognition, we have launched the ManyDogs consortium, modeled on similar ManyX projects in other fields. We aimed to create a collaborative network that (a) uses large, diverse samples to investigate and replicate findings, (b) promotes open science practices of pre-registering hypotheses, methods, and analysis plans, (c) investigates the influence of differences across populations and breeds, and (d) examines how different research methods and testing environments influence the robustness of results. Our first study combines a phenomenon that appears to be highly reliable—dogs’ ability to follow human pointing—with a question that remains controversial: do dogs interpret pointing as a social communicative gesture or as a simple associative cue? We collected data (N = 455) from 20 research sites on two conditions of a 2-alternative object choice task: (1) Ostensive (pointing to a baited cup after making eye-contact and saying the dog’s name); (2) Non-ostensive (pointing without eye-contact, after a throat-clearing auditory control cue). Comparing performance between conditions, while both were significantly above chance, there was no significant difference in dogs’ responses. This result was consistent across sites. Further, we found that dogs followed contralateral, momentary pointing at lower rates than has been reported in prior research, suggesting that there are limits to the robustness of point-following behavior: not all pointing styles are equally likely to elicit a response. Together, these findings underscore the important role of procedural details in study design and the broader need for replication studies in canine science.

Background:. The demonstrated benefits of virtual reality (VR) in orthopaedic surgical training are numerous. However, it is relatively unknown how best to implement VR into an already established orthopaedic resident education curriculum and how trainees will engage and use these technologies longitudinally. Methods:. This was an exploratory, qualitative research study performed in accordance with Consolidated Criteria for Reporting Qualitative Research guidelines. Orthopaedic surgery residents at a single institution were recruited during the 2022 to 2023 academic year. Semistructured interviews were conducted. Data were analyzed through grounded theory methodology, beginning with open coding, followed by axial coding, and concluding with selective coding that describes orthopaedic surgery residents' current perceptions of VR as a training tool. Results:. Six residents participated in interviews before thematic saturation was achieved. Average interview length was 13:27 (±2:59) minutes. Residents felt that currently, VR is most useful for interns and junior residents as an educational adjunct for learning anatomy, surgical exposures, and the steps of a procedure in a risk- and judgment-free arena. There seems to be a “ceiling effect” with VR given current technological limitations, and residents remarked that there is an associated “opportunity cost” with using VR technology. Some residents may find it more time-efficient to study texts, videos, or surgical guides rather than use VR. Cost (limited number of headsets) and technological barriers (i.e., hardware, software, and Wi-Fi issues) were some of the described barriers to VR utilization. Residents felt that there needs to be dedicated technological support to help with these issues. At this time, given these limitations of VR, many preferred VR as an optional educational adjunct rather than as a required curricular tool or assessment of surgical competency. Conclusions:. There is current utility for VR in orthopaedic surgical training. Future technological advances may make VR more central to resident education. This study describes resident perceptions about the technology and best use practices for the technology. Level of Evidence:. Qualitative Study, Level V Evidence

Background:. COVID-19 forced surgical resident training programs to adapt to meet educational requirements within the constraints of various guidelines. Some of the changes implemented during the pandemic have imparted a lasting effect on orthopaedic education. As such, the purpose of this article was to review how orthopaedic training and education were affected during the COVID-19 pandemic. Methods:. The published literature was queried using search strategies devised by a medical librarian, according to the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Studies eligible for inclusion were studies related to COVID-19, orthopaedic surgical training, and medical education. Studies were excluded if they (1) were abstracts, conference proceedings, letters, perspective pieces, reviews, or editorials; (2) evaluated medical student education; (3) included other specialties; or (4) were unrelated to COVID-19 and/or orthopaedic training. Results:. Eighty-three (n = 83) studies were included. Five themes emerged including (I) Fellowship Application, Interview, and Match Processes; (II) Social Media and Websites for Program Information; (III) Changes in Trainee Surgical Volume; (IV) Trainee Mental Health and Well-being; and (V) Innovations in Education. The pandemic decreased opportunities for medical students to gain exposure to orthopaedic surgery. Social media use, particularly Instagram, among orthopaedic residencies increased during the pandemic. Between the cancellation of away rotations and in-person interviews, applicants saved over $6,000; however, both residency applicants and interviewers preferred in-person interviews. The pandemic led to decreased surgical volume and in-person didactics for trainees, thus relying more on virtual learning. Orthopaedic trainees had mixed feelings regarding online virtual education. Although some respondents reported that they preferred the convenience of online learning, others expressed dissatisfaction with the quality of virtual education. Conclusions:. The shift to virtual learning affected how applicants learned about residency programs, with many relying on virtual away rotations and social media to compare different programs. The pandemic also highlighted issues of diversity and accessibility within orthopaedic surgery, with cost savings from virtual interviews and canceled away rotations potentially benefiting applicants from lower socioeconomic backgrounds. Although some innovative approaches and adaptations to orthopaedic education and training have shown promise and may continue to be used in the future after the COVID-19 pandemic, the role of others, such as virtual interviews, is less clear.

Abstract Background Cachexia is frequent, deadly, and untreatable for patients with pancreatic ductal adenocarcinoma (PDAC). The reproductive hormone and cytokine Activin is a mediator of PDAC cachexia, and Activin receptor targeting was clinically tested for cancer cachexia therapy. However, sex‐specific manifestations and mechanisms are poorly understood, constraining development of effective treatments. Methods Cachexia phenotypes, muscle gene/protein expression, and effects of the Activin blocker ACVR2B/Fc were assessed in LSL‐KrasG12D/+, LSL‐Trp53R172H/+, and Pdx‐1‐Cre (KPC) mice with autochthonic PDAC. Effects of PDAC and sex hormones were modelled by treating C2C12 myotubes with KPC‐cell conditioned medium (CM) and estradiol. Muscle gene expression by RNAseq and change in muscle from serial CT scans were measured in patients with PDAC. Results Despite equivalent tumour latency (median 17 weeks) and mortality (24.5 weeks), male KPC mice showed earlier and more severe cachexia than females. In early PDAC, male gastrocnemius, quadriceps, and tibialis anterior muscles were reduced (−21.7%, −18.9%, and −20.8%, respectively, all P

Summary: Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.

Many postsecondary education institutions in the United States struggle to effectively support high levels of academic achievement and college completion among their students. This is especially true at less selective and online colleges and universities that are understudied but serve an increasing number of students. Psychological factors may play an important role in promoting positive student outcomes during the college years. Two randomized controlled experiments including online university students focused on the potential influence of opportunities for students to reflect upon their future identities or ideas about their lives in the years to come. In Study 1 (N = 1,042), a course activity designed to engage students’ future identities showed positive effects on course grades and persistence in college during the next semester. In Study 2 (N = 2,515), a more rigorous design demonstrated the effects of activating future identities on specific motivational processes with positive consequences for academic outcomes. Together, the experiments suggest that educators and advisors should engage with how students imagine their futures in order to help support student success.

Abstract Background Several lines of evidence suggest that high-density lipoprotein (HDL) reduces Alzheimer’s disease (AD) risk by decreasing vascular beta-amyloid (Aβ) deposition and inflammation, however, the mechanisms by which HDL improve cerebrovascular functions relevant to AD remain poorly understood. Methods Here we use a human bioengineered model of cerebral amyloid angiopathy (CAA) to define several mechanisms by which HDL reduces Aβ deposition within the vasculature and attenuates endothelial inflammation as measured by monocyte binding. Results We demonstrate that HDL reduces vascular Aβ accumulation independently of its principal binding protein, scavenger receptor (SR)-BI, in contrast to the SR-BI-dependent mechanism by which HDL prevents Aβ-induced vascular inflammation. We describe multiple novel mechanisms by which HDL acts to reduce CAA, namely: i) altering Aβ binding to collagen-I, ii) forming a complex with Aβ that maintains its solubility, iii) lowering collagen-I protein levels produced by smooth-muscle cells (SMC), and iv) attenuating Aβ uptake into SMC that associates with reduced low density lipoprotein related protein 1 (LRP1) levels. Furthermore, we show that HDL particles enriched in apolipoprotein (apo)E appear to be the major drivers of these effects, providing new insights into the peripheral role of apoE in AD, in particular, the fraction of HDL that contains apoE. Conclusion The findings in this study identify new mechanisms by which circulating HDL, particularly HDL particles enriched in apoE, may provide vascular resilience to Aβ and shed new light on a potential role of peripherally-acting apoE in AD.

We review observations of solar activity, geomagnetic variation, and auroral visibility for the extreme geomagnetic storm on 1872 February 4. The extreme storm (referred to here as the Chapman–Silverman storm) apparently originated from a complex active region of moderate area (≈ 500 μ sh) that was favorably situated near disk center (S19° E05°). There is circumstantial evidence for an eruption from this region at 9–10 UT on 1872 February 3, based on the location, complexity, and evolution of the region, and on reports of prominence activations, which yields a plausible transit time of ≈29 hr to Earth. Magnetograms show that the storm began with a sudden commencement at ≈14:27 UT and allow a minimum Dst estimate of ≤ −834 nT. Overhead aurorae were credibly reported at Jacobabad (British India) and Shanghai (China), both at 19.°9 in magnetic latitude (MLAT) and 24.°2 in invariant latitude (ILAT). Auroral visibility was reported from 13 locations with MLAT below ∣20∣° for the 1872 storm (ranging from ∣10.°0∣–∣19.°9∣ MLAT) versus one each for the 1859 storm (∣17.°3∣ MLAT) and the 1921 storm (∣16.°2∣ MLAT). The auroral extension and conservative storm intensity indicate a magnetic storm of comparable strength to the extreme storms of 1859 September (25.°1 ± 0.°5 ILAT and −949 ± 31 nT) and 1921 May (27.°1 ILAT and −907 ± 132 nT), which places the 1872 storm among the three largest magnetic storms yet observed.

Abstract Background Polyadenylation plays a key role in producing mature mRNAs in eukaryotes. It is widely believed that the poly(A)-binding proteins (PABs) uniformly bind to poly(A)-tailed mRNAs, regulating their stability and translational efficiency. Results We observe that the homozygous triple mutant of broadly expressed Arabidopsis thaliana PABs, AtPAB2, AtPAB4, and AtPAB8, is embryonic lethal. To understand the molecular basis, we characterize the RNA-binding landscape of these PABs. The AtPAB-binding efficiency varies over one order of magnitude among genes. To identify the sequences accounting for the variation, we perform poly(A)-seq that directly sequences the full-length poly(A) tails. More than 10% of poly(A) tails contain at least one guanosine (G); among them, the G-content varies from 0.8 to 28%. These guanosines frequently divide poly(A) tails into interspersed A-tracts and therefore cause the variation in the AtPAB-binding efficiency among genes. Ribo-seq and genome-wide RNA stability assays show that AtPAB-binding efficiency of a gene is positively correlated with translational efficiency rather than mRNA stability. Consistently, genes with stronger AtPAB binding exhibit a greater reduction in translational efficiency when AtPAB is depleted. Conclusions Our study provides a new mechanism that translational efficiency of a gene can be regulated through the G-content-dependent PAB binding, paving the way for a better understanding of poly(A) tail-associated regulation of gene expression.

How cellular noise impacts metabolic trade-offs remains unknown. Here, the authors use a quantitative single-cell mass imaging strategy to reveal that cellular noise impacts cellular biomass and triacylglycerol accumulation, as well as protein and fatty-acid recycling under starvation, differently.