Development and validation of a deep learning-based microsatellite instability predictor from prostate cancer whole-slide images.

Microsatellite instability-high (MSI-H) is a tumor-agnostic biomarker for immune checkpoint inhibitor therapy. However, MSI status is not routinely tested in prostate cancer, in part due to low prevalence and assay cost. As such, prediction of MSI status from hematoxylin and eosin (H&E) stained whole-slide images (WSIs) could identify prostate cancer patients most likely to benefit from confirmatory testing to evaluate their eligibility for immunotherapy and need for Lynch syndrome testing. Prostate biopsies and surgical resections from prostate cancer patients referred to our institution were analyzed. MSI status was determined by next-generation sequencing. Patients sequenced before a cutoff date formed an algorithm development set (n = 4015, MSI-H 1.8%) and a paired validation set (n = 173, MSI-H 19.7%) that consisted of two serial sections from each sample, one stained and scanned internally and the other at an external site. Patients sequenced after the cutoff date formed a temporally independent validation set (n = 1350, MSI-H 2.3%). Attention-based multiple instance learning models were trained to predict MSI-H from H&E WSIs. The predictor achieved area under the receiver operating characteristic curve values of 0.78 (95% CI [0.69-0.86]), 0.72 (95% CI [0.63-0.81]), and 0.72 (95% CI [0.62-0.82]) on the internally prepared, externally prepared, and temporal validation sets, respectively, showing effective predictability and generalization to both external staining/scanning processes and temporally independent samples. While MSI-H status is significantly correlated with Gleason score, the model remained predictive within each Gleason score subgroup.

Comparison of Graft Type and Fixation Method in Anterior Cruciate Ligament Reconstruction: A Systematic Review and Meta-analysis Based on Randomized Control Studies.

BACKGROUND: The anterior cruciate ligament (ACL) is the most commonly injured ligament in the knee. ACL reconstruction (ACLR) proves the standard for treating this injury. However, graft choice and method of fixation remain a heavily debated topic. This study investigates the following: bone-patellar tendon-bone (BPTB) vs. hamstring tendon (HT) autograft, single-bundle vs. double-bundle hamstring graft, and metal vs. bioabsorbable screws in ACLR. METHODS: A systematic review was performed on PubMed and Google Scholar according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were collected on patient demographics, complications, and functionality scores including International Knee Documentation Committee (IKDC) and Lysholm scores. A systematic review and meta-analysis were conducted with Review Manager. Outcome measurements were determined using forest plots with significant differences considered p < 0.05. RESULTS: Twenty-five studies were included, accounting for 2,170 patients. No statistically significant difference was appreciated when comparing BPTB to hamstring autografts. Patients who received a double bundle HT autograft exhibited significantly superior outcomes in terms of revision (p = 0.05), failure (p = 0.002), normal pivot shift tests (p = 0.04), and normal IKDC (p = 0.008). When comparing screw types, bioabsorbable screws had a greater Lysholm score (p = 0.01) and lower failure rates for copolymer screws (p = 0.03). CONCLUSION: Overall, the data collected suggested that BPTB and HT autografts display similar postoperative results. However, if an HT autograft is used, the data suggest a double-bundle graft improves both functionality and decreases the possible complications. Finally, bioabsorbable screws prove superior to metal screws when looking at both functionality and failure rates. Further research into the superior graft type is still needed. LEVEL OF EVIDENCE: Level II. See Instructions for Authors for a complete description of levels of evidence.

PharmaMemory: an interactive, animated web application for learning autonomic physiology and pharmacology.

Intro Medical students face challenging but important topics they must learn in short periods of time such as autonomic pharmacology. Autonomic pharmacology is difficult in that it requires students to synthesize detailed anatomy, physiology, clinical skills, and pharmacology. The subject poses a challenge to learn as it is often introduced early in the medical school curriculum. Methods To ease the difficulty of learning autonomic pharmacology, we created a free web application, PharmaMemory (www.pharmamemory.com) that interactively depicts the effects of high-yield autonomic drugs on the human body. PharmaMemory provides users with the opportunity to read about and quiz themselves on the mechanisms, side effects, indications, and contraindications of these drugs while interacting with the application. We provided PharmaMemory to first-year medical students for 2 consecutive years of quality improvement and assessed the application's perceived effects on learning via user surveys. Results Survey feedback showed users viewed PharmaMemory favorably and self-reported increased understanding, knowledge, and confidence in the subject of autonomic pharmacology. Comments were largely positive or constructive. Discussion PharmaMemory utilizes challenged recall, visual stimulation, and interactive learning to provide users with a multifaceted learning tool. Preliminary data suggest that students find this method of learning beneficial. Further studies are needed to assess PharmaMemory compared to more traditional learning methods such as PowerPoint or text-based learning. Additionally, further research is needed to quantitatively assess reduction in cognitive load.

Management of Locally Advanced Basal Cell Carcinoma with Sonic Hedgehog Pathway Targeted Therapy: A Case Report and Discussion.

Introduction: Basal cell carcinoma (BCC) is the most common skin malignancy in the world. While most lesions are treated using surgical methods, others may present as locally advanced or metastatic disease and are not amenable to surgical therapy alone. Treatment with sonic hedgehog pathway inhibitors (vismodegib, sonidegib) is designed to inhibit key signaling proteins and gene pathways involved with BCC to reduce the uncontrolled proliferation of basal cells in complicated disease and can be invaluable in treating patients with advanced disease. Case Presentation: We describe the course of a 68-year-old man who presented with a 7.2 × 6 cm exophytic and ulcerated locally invasive BCC of his upper back. The patient was started on daily vismodegib treatment with the goal of eventual surgical resection. After 11 weeks of therapy, he had significant improvement in both wound size and appearance. After 18 weeks of therapy, he had achieved a near complete clinical response of the central aspect of lesion with three remaining small peripheral lesions. These lesions were biopsied, and two were found to be negative for malignancy, while a small inferior nodule was positive for squamous cell carcinoma (SCC). Vismodegib therapy was discontinued after a total of 26 weeks of therapy. Excision of the SCC was performed, and the patient remains disease free at 2 years. Conclusion: This case report shows the efficacy of hedgehog pathway inhibitor therapy in the treatment of a locally advanced BCC with complete pathologic response, not requiring surgical intervention.

The therapeutic potential of immunoengineering for systemic autoimmunity.

Disease-modifying drugs have transformed the treatment options for many systemic autoimmune diseases. However, an evolving understanding of disease mechanisms, which might vary between individuals, is paving the way for the development of novel agents that operate in a patient-tailored manner through immunophenotypic regulation of disease-relevant cells and the microenvironment of affected tissue domains. Immunoengineering is a field that is focused on the application of engineering principles to the modulation of the immune system, and it could enable future personalized and immunoregulatory therapies for rheumatic diseases. An important aspect of immunoengineering is the harnessing of material chemistries to design technologies that span immunologically relevant length scales, to enhance or suppress immune responses by re-balancing effector and regulatory mechanisms in innate or adaptive immunity and rescue abnormalities underlying pathogenic inflammation. These materials are endowed with physicochemical properties that enable features such as localization in immune cells and organs, sustained delivery of immunoregulatory agents, and mimicry of key functions of lymphoid tissue. Immunoengineering applications already exist for disease management, and there is potential for this new discipline to improve disease modification in rheumatology.

Expanded Systematic Evidence Map for Hundreds of Per- and Polyfluoroalkyl Substances (PFAS) and Comprehensive PFAS Human Health Dashboard.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) encompass a class of chemically and structurally diverse compounds that are extensively used in industry and detected in the environment. The US Environmental Protection Agency (US EPA) 2021 PFAS Strategic Roadmap describes national research plans to address the challenge of PFAS. OBJECTIVES: Systematic Evidence Map (SEM) methods were used to survey and summarize available epidemiological and mammalian bioassay evidence that could inform human health hazard identification for a set of 345 PFAS that were identified by the US EPA's Center for Computational Toxicology and Exposure (CCTE) for in vitro toxicity and toxicokinetic assay testing and through interagency discussions on PFAS of interest. This work builds from the 2022 evidence map that collated evidence on a separate set of ∼150 PFAS. Like our previous work, this SEM does not include PFAS that are the subject of ongoing or completed assessments at the US EPA. METHODS: SEM methods were used to search, screen, and inventory mammalian bioassay and epidemiological literature from peer-reviewed and gray literature sources using manual review and machine-learning software. For each included study, study design details and health end points examined were summarized in interactive web-based literature inventories. Some included studies also underwent study evaluation and detailed extraction of health end point data. All underlying data is publicly available online as interactive visuals with downloadable metadata. RESULTS: More than 13,000 studies were identified from scientific databases. Screening processes identified 121 mammalian bioassay and 111 epidemiological studies that met screening criteria. Epidemiological evidence (available for 12 PFAS) mostly assessed the reproductive, endocrine, developmental, metabolic, cardiovascular, and immune systems. Mammalian bioassay evidence (available for 30 PFAS) commonly assessed effects in the reproductive, whole-body, nervous, and hepatic systems. Overall, 41 PFAS had evidence across mammalian bioassay and epidemiology data streams (roughly 11% of searched chemicals). DISCUSSION: No epidemiological and/or mammalian bioassay evidence were identified for most of the PFAS included in our search. Results from this SEM, our 2022 SEM on ∼150 PFAS, and other PFAS assessment products from the US EPA are compiled into a comprehensive PFAS dashboard that provides researchers and regulators an overview of the current PFAS human health landscape including data gaps and can serve as a scoping tool to facilitate prioritization of PFAS-related research and/or risk assessment activities. https://doi.org/10.1289/EHP13423.

Incidence and risk factors of peri-operative stroke in major non-cardiovascular, non-neurologic surgery-A retrospective register-based cohort study.

BACKGROUND: Peri-operative stroke is a rare but serious surgical complication. Both overt and covert stroke, occurring in approximately 0.1% and 7% of cases, respectively, are associated with significant long-term effects and increased morbidity. METHODS: Retrospective register data for patients >18 years old, presenting for major non-cardiovascular, non-neurosurgical and non-ambulatory surgical procedures at 23 hospitals in Sweden between 2007 and 2014 was collected and linked with various quality registers. The primary outcome was stroke within 30 days from surgery. Using multivariable logistic regression, significant independent risk factors influencing the primary outcome were identified and their adjusted odds ratios (ORs) were calculated. Mortality was assessed, along with the composite score of days alive and at home within 30 days after surgery (DAH 30). RESULTS: In total, 318,017 patients were included, with 687 (0.22%) suffering a stroke within 30 days of surgery. The strongest significant risk factors included: increasing ASA-class (OR [95% confidence interval, CI]: 2.23 [1.53-3.36], 3.91 [2.68-5.93] and 7.82 [5.03-12.5] for ASA 2, 3 and 4, respectively) and age (OR [95% CI]: 4.47 [2.21-10.3], 9.9 [5.15-22.1], 16.3 [8.48-36.5] and 21 [10.6-48.1], for age 45-59, 60-74, 75-89 and >90, respectively), along with non-elective procedures, male gender and a history of cerebrovascular disease (OR [95%]: 2.72 [2.25-3.27]). Mortality was increased and DAH 30 was reduced in patients suffering a stroke. CONCLUSIONS: Increasing ASA-class and age was clearly associated with an increased risk of peri-operative stroke, which in turn was associated with increased mortality and poorer outcome. Detailed pre-operative risk stratification and individualised peri-operative management could potentially improve patient-centred outcomes and, in turn, have positive implications for public health.

Inflammatory Rhabdomyoblastic Tumor of the Posterior Pharyngeal Wall.

This case report describes a healthy man in his 40s who presented with a 1-year history of snoring, sleep apnea, dysphonia, and dysphagia owing to a large mass of the posterior pharynx and was diagnosed with an inflammatory rhabdomyoblastic tumor.

Immunomodulatory Nanoparticles for Modulating Arthritis Flares.

Disease-modifying drugs have improved the treatment for autoimmune joint disorders, such as rheumatoid arthritis, but inflammatory flares are a common experience. This work reports the development and application of flare-modulating poly(lactic-co-glycolic acid)-poly(ethylene glycol)-maleimide (PLGA-PEG-MAL)-based nanoparticles conjugated with joint-relevant peptide antigens, aggrecan70-84 and type 2 bovine collagen256-270. Peptide-conjugated PLGA-PEG-MAL nanoparticles encapsulated calcitriol, which acted as an immunoregulatory agent, and were termed calcitriol-loaded nanoparticles (CLNP). CLNP had a ∼200 nm hydrodynamic diameter with a low polydispersity index. In vitro, CLNP induced phenotypic changes in bone marrow derived dendritic cells (DC), reducing the expression of costimulatory and major histocompatibility complex class II molecules, and proinflammatory cytokines. Bulk RNA sequencing of DC showed that CLNP enhanced expression of Ctla4, a gene associated with downregulation of immune responses. In vivo, CLNP accumulated in the proximal lymph nodes after intramuscular injection. Administration of CLNP was not associated with changes in peripheral blood cell numbers or cytokine levels. In the collagen-induced arthritis and SKG mouse models of autoimmune joint disorders, CLNP reduced clinical scores, prevented bone erosion, and preserved cartilage proteoglycan, as assessed by high-resolution microcomputed tomography and histomorphometry analysis. The disease protective effects were associated with increased CTLA-4 expression in joint-localized DC and CD4+ T cells but without generalized suppression of T cell-dependent immune response. The results support the potential of CLNP as modulators of disease flares in autoimmune arthropathies.

Auditory masking in odobenid and otariid carnivoresa).

As the only living species within the odobenid lineage of carnivores, walruses (Odobenus rosmarus) have no close relatives from which auditory information can be extrapolated. Sea lions and fur seals in the otariid lineage are the nearest evolutionary outgroup. To advance understanding of odobenid and otariid hearing, we conducted behavioral testing with two walruses and one California sea lion (Zalophus californianus). Detection thresholds for airborne sounds were measured from 0.08 to at least 16 kHz in ambient noise conditions and then re-measured in the presence of octave-band white masking noise. Walruses were more sensitive than the sea lion at lower frequencies and less sensitive at higher frequencies. Critical ratios for the walruses ranged from 20 dB at 0.2 kHz to 32 dB at 10 kHz, while critical ratios for the sea lion ranged from 16 dB at 0.2 kHz to 35 dB at 32 kHz. The masking values for these species are comparable to one another and to those of terrestrial carnivores, increasing by about 3 dB per octave with increasing frequency. Despite apparent differences in hearing range and sensitivity, odobenids and otariids have a similar ability to hear signals in noisy conditions.

Three-dimensional super resolution ultrasound imaging with a multi-frequency hemispherical phased array.

BACKGROUND: High resolution imaging of the microvasculature plays an important role in both diagnostic and therapeutic applications in the brain. However, ultrasound pulse-echo sonography imaging the brain vasculatures has been limited to narrow acoustic windows and low frequencies due to the distortion of the skull bone, which sacrifices axial resolution since it is pulse length dependent. PURPOSE: To overcome the detect limit, a large aperture 256-module sparse hemispherical transmit/receive array was used to visualize the acoustic emissions of ultrasound-vaporized lipid-coated decafluorobutane nanodroplets flowing through tube phantoms and within rabbit cerebral vasculature in vivo via passive acoustic mapping and super resolution techniques. METHODS: Nanodroplets were vaporized with 55 kHz burst-mode ultrasound (burst length = 145 µs, burst repetition frequency = 9-45 Hz, peak negative acoustic pressure = 0.10-0.22 MPa), which propagates through overlying tissues well without suffering from severe distortions. The resulting emissions were received at a higher frequency (612 or 1224 kHz subarray) to improve the resulting spatial resolution during passive beamforming. Normal resolution three-dimensional images were formed using a delay, sum, and integrate beamforming algorithm, and super-resolved images were extracted via Gaussian fitting of the estimated point-spread-function to the normal resolution data. RESULTS: With super resolution techniques, the mean lateral (axial) full-width-at-half-maximum image intensity was 16 ± 3 (32 ± 6) µm, and 7 ± 1 (15 ± 2) µm corresponding to ∼1/67 of the normal resolution at 612 and 1224 kHz, respectively. The mean positional uncertainties were ∼1/350 (lateral) and ∼1/180 (axial) of the receive wavelength in water. In addition, a temporal correlation between nanodroplet vaporization and the transmit waveform shape was observed, which may provide the opportunity to enhance the signal-to-noise ratio in future studies. CONCLUSIONS: Here, we demonstrate the feasibility of vaporizing nanodroplets via low frequency ultrasound and simultaneously performing spatial mapping via passive beamforming at higher frequencies to improve the resulting spatial resolution of super resolution imaging techniques. This method may enable complete four-dimensional vascular mapping in organs where a hemispherical array could be positioned to surround the target, such as the brain, breast, or testicles.

Emissions and energy impacts of the Inflation Reduction Act.

Economy-wide emissions drop 43 to 48% below 2005 levels by 2035 with accelerated clean energy deployment.

Emergence of Treadmill Running Ability and Quantitative Assessment of Gait Dynamics in Young Ts65Dn Mice: A Mouse Model for Down Syndrome.

Down syndrome (DS), which results from the complete or partial trisomy of chromosome 21 (trisomy-21), is the most common genetically defined cause of intellectual disability. Trisomy-21 also produces, or is associated with, many neurodevelopmental phenotypes and neurological comorbidities, including delays and deficits in fine and gross motor development. The Ts65Dn mouse is the most studied animal model for DS and displays the largest known subset of DS-like phenotypes. To date, however, only a small number of developmental phenotypes have been quantitatively defined in these animals. Here, we used a commercially available high-speed, video-based system to record and analyze the gait of Ts65Dn and euploid control mice. Longitudinal treadmill recordings were performed from p17 to p35. One of the main findings was the detection of genotype- and sex-dependent developmental delays in the emergence of consistent, progressive-intensity gait in Ts65Dn mice when compared to control mice. Gait dynamic analysis showed wider normalized front and hind stances in Ts65Dn mice compared to control mice, which may reflect deficits in dynamic postural balance. Ts65Dn mice also displayed statistically significant differences in the variability in several normalized gait measures, which were indicative of deficits in precise motor control in generating gait.

Validation of a Transcriptome-Based Assay for Classifying Cancers of Unknown Primary Origin.

INTRODUCTION: Cancers assume a variety of distinct histologies, and may originate from a myriad of sites including solid organs, hematopoietic cells, and connective tissue. Clinical decision-making based on consensus guidelines such as the National Comprehensive Cancer Network (NCCN) is often predicated on a specific histologic and anatomic diagnosis, supported by clinical features and pathologist interpretation of morphology and immunohistochemical (IHC) staining patterns. However, in patients with nonspecific morphologic and IHC findings-in addition to ambiguous clinical presentations such as recurrence versus new primary-a definitive diagnosis may not be possible, resulting in the patient being categorized as having a cancer of unknown primary (CUP). Therapeutic options and clinical outcomes are poor for patients with CUP, with a median survival of 8-11 months. METHODS: Here, we describe and validate the Tempus Tumor Origin (Tempus TO) assay, an RNA-sequencing-based machine learning classifier capable of discriminating between 68 clinically relevant cancer subtypes. Model accuracy was assessed using primary and/or metastatic samples with known subtype. RESULTS: We show that the Tempus TO model is 91% accurate when assessed on both a retrospectively held out cohort and a set of samples sequenced after model freeze that collectively contained 9210 total samples with known diagnoses. When evaluated on a cohort of CUPs, the model recapitulated established associations between genomic alterations and cancer subtype. DISCUSSION: Combining diagnostic prediction tests (e.g., Tempus TO) with sequencing-based variant reporting (e.g., Tempus xT) may expand therapeutic options for patients with cancers of unknown primary or uncertain histology.

Aborted sudden cardiac death and a severe form of hypertrophic cardiomyopathy in a 2-year-old.

Although hypertrophic cardiomyopathy has a reported prevalence of 1/500, compound, double, and triple mutations are infrequent. There is phenotypic variation between individuals with HCM, making disease course difficult to predict. There is some debate as to whether multiple mutations confer a worse prognosis and the extent to which the mutations affect an individual's prognosis. We report a case of homozygous MYBPC3 mutations in a 2-year-old presenting with aborted sudden cardiac death and a severe form of hypertrophic cardiomyopathy.

Predictors of methamphetamine use in a longitudinal birth cohort.

BACKGROUND: Identifying predictors of methamphetamine use can inform population prevention strategies. METHODS: Participants (n = 1265) born in Christchurch, New Zealand were followed from birth to age 40. Methamphetamine outcomes (any use since the last interview, and regular use, defined as any period of at least weekly use) were ascertained by self-report at six interviews from age 18 to 40. Predictors with plausible associations with methamphetamine use were extracted from the study database. These were grouped into early predictors (age 0-16), comprising childhood, familial and individual characteristics; and later time-dynamic correlates of methamphetamine use in adulthood (ages 16-40). Generalised estimating equation models were fitted to identify predictors of methamphetamine use outcomes. RESULTS: In adjusted models, paternal overprotectiveness and childhood anxious / withdrawn behavior were associated with any use of methamphetamine, but not regular use. Conversely, childhood conduct problems and parental illicit drug were associated with regular use but not any use. Male sex, high novelty seeking and deviant peer affiliations were associated with both any use and regular use in adjusted models. The strongest correlates of methamphetamine use in adulthood were unemployment, life stress and other substance use disorders (cannabis, nicotine, and alcohol). CONCLUSION: Markers of externalizing problems in childhood and adolescence (conduct problems, high novelty seeking, parental illicit substance use, and deviant peer affiliations) are the strongest predictors of regular methamphetamine use in adulthood.