Fine Needle Aspiration Cytology of Pancreatoblastoma in Adult/Adolescent Patients, One With Histology Mimicking NUT Carcinoma.

Pancreatoblastoma is a rare malignant neoplasm. Cytologic diagnosis is challenging due to the tumor's heterogeneity and requirement of the presence of squamoid nests. Commonly affects children, but the tumor rarely is seen in adult patients. We are reporting three cases from two patients. First patient was a 38-year-old male with a mass in the pancreatic body and numerous hepatic lesions. Fine-needle aspiration (FNA) of the pancreas showed a biphasic malignancy, predominantly composed of a primitive component with intermingled squamoid nests. Subsequent Liver FNA from the same patient showed a similar biphasic malignancy. NUT carcinoma was the top differential and was ruled out by molecular testing. Second patient was a 24-year-old female with a history of pancreatoblastoma related to Gardner's syndrome initially diagnosed in 2015 at age 17, status post distal pancreatectomy and chemotherapy. Celiac lymph node FNA in 2021 showed few cohesive clusters of atypical epithelioid cells, which were highlighted by beta-catenin. Lastly, the literature was reviewed; differential diagnosis and ancillary testing were discussed.

Barriers to auditory brainstem response testing under anesthesia.

OBJECTIVE: Auditory brainstem response (ABR) testing is the gold standard for diagnosis of hearing loss in children who cannot complete behavioral audiometry. Testing under general anesthesia is often recommended when natural sleep ABR and/or behavioral audiometry are unsuccessful. This study aims to determine which demographic and patient factors serve as barriers to receiving this diagnostic testing. METHODS: A retrospective chart review from an internal database of patients who underwent ABR testing under anesthesia from 2017 to 2023 was completed. Patient demographics, clinical diagnoses, dates of initial recommendation, and dates of testing were recorded. RESULTS: A total of 395 patients met inclusion criteria, with a median time from initial evaluation to successful ABR under anesthesia of 5.1 months (range 0.1-209 months). This time was significantly higher in patients with public insurance compared to private insurance and in patients with the following medical complexities: cardiac disease, developmental delay, neurologic disease, eye disease, and genetic syndromes not associated with hearing loss. The interval was significantly shorter in patients with abnormal ear anatomy. CONCLUSION: Patient factors, such as insurance type and certain medical diagnoses, may lead to delayed ABR testing under anesthesia and thus delayed diagnosis and management of hearing loss. This has implications for the timely care and treatment of children with hearing loss.

Intestinal distribution of anionic, cationic, and neutral polymer-stabilized nanocarriers measured with a lanthanide (europium) tracer assay.

Nanocarriers, more commonly called nanoparticles (NPs), have found increasing use as delivery vehicles which increase the oral bioavailability of poorly water-soluble and peptide therapeutics. Therapeutic bioavailability is commonly assessed by measuring plasma concentrations that reflect the absorption kinetics. This bioavailability is a convolution of the gastrointestinal distribution of the NP vehicle, the release rate of the encapsulated therapeutic cargo, and the absorption-metabolism-distribution kinetics of the released therapeutic. The spatiotemporal distribution of the NP vehicle in the gastrointestinal tract is not well studied and is a buried parameter in PK studies used to measure the effectiveness of an NP formulation. This work is a study of the intestinal distribution and fate of orally dosed NPs in male CD-1 mice over 24 h. NPs have identical hydrophobic cores - composed of poly(styrene) homopolymer, a naphthalocyanine dye, and oleate-coated europium oxide colloids - with one of four different surface stabilizers: neutral poly(styrene)-block-poly(ethylene glycol) (PS-b-PEG), moderately negative hydroxypropyl methylcellulose acetate succinate (HPMCAS), highly negative poly(styrene)-block-poly(acrylic acid) (PS-b-PAA), and highly cationic adsorbed chitosan HCl on PS-b-PAA stabilized NPs. NP hydrodynamic diameters are all below 200 nm (nm), with some variation attributable to the molecular properties of the stabilizing polymer. The encapsulated hydrophobic europium oxide colloids do not release soluble europium ions, enabling the use of highly sensitive inductively coupled plasma mass spectrometry (ICP-MS) to detect NP concentrations in digested biological tissues. Highly charged PAA (60 % more) and chitosan (50 % more) stabilized NPs showed statistically significant increased retention compared to the neutral PEG-stabilized NPs at p < 0.05 significance and (1-ß) > 0.95 power. HPMCAS-stabilized NPs showed statistically insignificant (16 % more) retention than PEG-stabilized NPs, and all NP formulations showed clearance from the intestines within 24 h. Different surface charges preferentially reside in different segments of the intestines, where cationic chitosan-stabilized NPs showed increased retention in the small intestines (ileum) and anionic PAA-stabilized NPs in the large intestines (caecum and colon). Modifying the surface charge of a NP can be used to modulate mucoadhesion, total retention, and intestinal segment specific retention, which enables the rational design of delivery vehicles that maximize residence times in appropriate locations.

Importance of variables from different time frames for predicting self-harm using health system data.

Objective: Self-harm risk prediction models developed using health system data (electronic health records and insurance claims information) often use patient information from up to several years prior to the index visit when the prediction is made. Measurements from some time periods may not be available for all patients. Using the framework of algorithm-agnostic variable importance, we study the predictive potential of variables corresponding to different time horizons prior to the index visit and demonstrate the application of variable importance techniques in the biomedical informatics setting. Materials and Methods: We use variable importance to quantify the potential of recent (up to three months before the index visit) and distant (more than one year before the index visit) patient mental health information for predicting self-harm risk using data from seven health systems. We quantify importance as the decrease in predictiveness when the variable set of interest is excluded from the prediction task. We define predictiveness using discriminative metrics: area under the receiver operating characteristic curve (AUC), sensitivity, and positive predictive value. Results: Mental health predictors corresponding to the three months prior to the index visit show strong signal of importance; in one setting, excluding these variables decreased AUC from 0.85 to 0.77. Predictors corresponding to more distant information were less important. Discussion: Predictors from the months immediately preceding the index visit are highly important. Implementation of self-harm prediction models may be challenging in settings where recent data are not completely available (e.g., due to lags in insurance claims processing) at the time a prediction is made. Conclusion: Clinically derived variables from different time frames exhibit varying levels of importance for predicting self-harm. Variable importance analyses can inform whether and how to implement risk prediction models into clinical practice given real-world data limitations. These analyses be applied more broadly in biomedical informatics research to provide insight into general clinical risk prediction tasks.

DEK regulates B-cell proliferative capacity and is associated with aggressive disease in low-grade B-cell lymphomas.

This study sheds light on the pivotal role of the oncoprotein DEK in B-cell lymphoma. We reveal DEK expression correlates with increased tumor proliferation and inferior overall survival in cases diagnosed with low-grade B-cell lymphoma (LGBCL). We also found significant correlation between DEK expression and copy number alterations in LGBCL tumors, highlighting a novel mechanism of LGBCL pathogenesis that warrants additional exploration. To interrogate the mechanistic role of DEK in B-cell lymphoma, we generated a DEK knockout cell line model, which demonstrated DEK depletion caused reduced proliferation and altered expression of key cell cycle and apoptosis-related proteins, including Bcl-2, Bcl-xL, and p53. Notably, DEK depleted cells showed increased sensitivity to apoptosis-inducing agents, including venetoclax and staurosporine, which underscores the therapeutic potential of targeting DEK in B-cell lymphomas. Overall, our study contributes to a better understanding of DEK's role as an oncoprotein in B-cell lymphomas, highlighting its potential as both a promising therapeutic target and a novel biomarker for aggressive LGBCL. Further research elucidating the molecular mechanisms underlying DEK-mediated tumorigenesis could pave the way for improved treatment strategies and better clinical outcomes for patients with B-cell lymphoma.

SARS-CoV-2 variant replacement constrains vaccine-specific viral diversification.

Coronavirus disease 2019 (COVID-19) vaccine breakthrough infections have been important for all circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant periods, but the contribution of vaccine-specific SARS-CoV-2 viral diversification to vaccine failure remains unclear. This study analyzed 595 SARS-CoV-2 sequences collected from the Military Health System beneficiaries between December 2020 and April 2022 to investigate the impact of vaccination on viral diversity. By comparing sequences based on the vaccination status of the participant, we found limited evidence indicating that vaccination was associated with increased viral diversity in the SARS-CoV-2 spike, and we show little to no evidence of a substantial sieve effect within major variants; rather, we show that rapid variant replacement constrained intragenotype COVID-19 vaccine strain immune escape. These data suggest that, during past and perhaps future periods of rapid SARS-CoV-2 variant replacement, vaccine-mediated effects were subsumed with other drivers of viral diversity due to the massive scale of infections and vaccinations that occurred in a short time frame. However, our results also highlight some limitations of using sieve analysis methods outside of placebo-controlled clinical trials.

Cryo-EM structure of Alzheimer's disease tau filaments with PET ligand MK-6240.

Positron Emission Tomography (PET) ligands have advanced Alzheimer's disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identify AD brain tissue with elevated tau burden, purify filaments, and determine the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine 353, and isoleucine 360. This information elucidates the basis of MK-6240 PET in quantifying PHF deposits in AD and may facilitate the structure-based design of superior ligands against tau amyloids.

The impact of short-lived controls on the interpretation of lifespan experiments and progress in geroscience - through the lens of the "900-day rule".

Although lifespan extension remains the gold standard for assessing interventions proposed to impact the biology of aging, there are important limitations to this approach. Our reanalysis of lifespan studies from multiple sources suggests that short lifespans in the control group exaggerate the relative efficacy of putative longevity interventions. Results may be exaggerated due to statistical effects (e.g. regression to the mean) or other factors. Moreover, due to the high cost and long timeframes of mouse studies, it is rare that a particular longevity intervention will be independently replicated by multiple groups. To facilitate identification of successful interventions, we propose an alternative approach particularly suitable for well-characterized inbred and HET3 mice. The level of confidence we can have in an intervention is proportional to the degree of lifespan extension above the strain- and species-specific upper limit of lifespan, which we can estimate from comparison to historical controls. In the absence of independent replication, a putative mouse longevity intervention should only be considered with high confidence when control median lifespans are close to 900 days or if the final lifespan of the treated group is considerably above 900 days. Using this "900-day rule" we identified several candidate interventions from the literature that merit follow-up studies.

Is prolonged operative time associated with postoperative complications in liver surgery? An international multicentre cohort study of 5424 patients.

BACKGROUND: The relation between operative time and postoperative complications in liver surgery is unclear. The aim of this study is to assess the impact of operative time on the development of postoperative complications in patients who underwent minimally invasive or open liver resections of various anatomical extent and technical difficulty levels. METHODS: In this retrospective cohort study, patients that underwent a right hemihepatectomy (RH), technically major resection (anatomically minor resection in segment 1, 4a, 7 or 8; TMR) or left lateral sectionectomy (LLS) between 2000 and 2022 were extracted from a multicenter database comprising the prospectively maintained databases of 31 centers in 13 countries. Minimally invasive procedures performed during the learning curve were omitted. Logistic regression models, performed separately for 9 different groups based on stratification by procedure type and allocated surgical approach, were used to assess the association between the fourth quartile of operative time (25% of patients with the longest operative time) and postoperative complications. RESULTS: Overall, 5424 patients were included: 1351 underwent RH (865 open, 373 laparoscopic and 113 robotic), 2821 TMR (1398 open, 1225 laparoscopic and 198 robotic), and 1252 LLS (241 open, 822 laparoscopic and 189 robotic). After adjusting for potential confounders (age, BMI, gender, ASA grade, previous abdominal surgery, disease type and extent, blood loss, Pringle, intraoperative transfusions and incidents), the fourth quartile of operative time, compared to the first three quartiles, was associated with an increased risk of postoperative complications after open, laparoscopic and robotic TMR (aOR 1.35, p = 0.031; aOR 1.74, p = 0.001 and aOR 3.11, p = 0.014, respectively), laparoscopic and robotic RH (aOR 1.98, p = 0.018 and aOR 3.28, p = 0.055, respectively) and solely laparoscopic LLS (aOR 1.69, p = 0.019). CONCLUSIONS: A prolonged operative time is associated with an increased risk of postoperative complications, although it remains to be defined if this is a causal relationship.

Proof-of-concept evaluation of next-generation sequencing-based liquid biopsy for non-invasive cancer detection in cats.

This proof-of-concept evaluation demonstrates that next-generation sequencing-based liquid biopsy can detect genomic alterations in the blood of cats with cancer and the absence of such alterations in the blood of presumably cancer-free cats. Two cats with cytologically confirmed lymphoma and nine presumably cancer-free cats were included in this analysis. Whole blood was collected from each subject and samples were subjected to DNA extraction, library preparation, and next-generation sequencing. Both cancer-diagnosed subjects had somatic copy number variants (a "cancer signal") identified in cell-free DNA, suggesting the current presence of cancer in these subjects. All nine presumably cancer-free subjects had unremarkable genomic profiles, suggesting the absence of cancer in these subjects. Liquid biopsy using next-generation sequencing of cell-free DNA allows for blood-based detection of cancer-associated genomic alterations in cats. Such technology has the potential to offer considerable utility in veterinary medicine, particularly for the non-invasive prioritization of small cell intestinal lymphoma versus inflammatory bowel disease in cats with gastrointestinal signs. This study lays the foundation for future studies to fully validate this type of testing for use in clinical practice.

The Odyssey of HOMER: Comparative Effectiveness Research on Medication for Opioid Use Disorder During the COVID-19 Pandemic.

The usual challenges of conducting primary care research, including randomized trials, have been exacerbated, and new ones identified, during the COVID-19 pandemic. HOMER (Home versus Office for Medication Enhanced Recovery; subsequently, Comparing Home, Office, and Telehealth Induction for Medication Enhanced Recovery) is a pragmatic, comparative-effectiveness research trial that aims to answer a key question from patients and clinicians: What is the best setting in which to start treatment with buprenorphine for opioid use disorder for this patient at this time? In this article, we describe the difficult journey to find the answer. The HOMER study began as a randomized trial comparing treatment outcomes in patients starting treatment with buprenorphine via induction at home (unobserved) vs in the office (observed, synchronous). The study aimed to enroll 1,000 participants from 100 diverse primary care practices associated with the State Networks of Colorado Ambulatory Practices and Partners and the American Academy of Family Physicians National Research Network. The research team faced unexpected challenges related to the COVID-19 pandemic and dramatic changes in the opioid epidemic. These challenges required changes to the study design, protocol, recruitment intensity, and funding conversations, as well as patience. As this is a participatory research study, we sought, documented, and responded to practice and patient requests for adaptations. Changes included adding a third study arm using telehealth induction (observed via telephone or video, synchronous) and switching to a comprehensive cohort design to answer meaningful patient-centered research questions. Using a narrative approach based on the Greek myth of Homer, we describe here the challenges and adaptations that have provided the opportunity for HOMER to thrive and find the way home. These clinical trial strategies may apply to other studies faced with similar cultural and extreme circumstances.

Segmental retinal arteritis in a case of presumed bilateral rifabutin-associated hypopyon uveitis.

Purpose: To describe the presentation and clinical course of bilateral hypopyon uveitis and subsequently diagnosed segmental retinal arteritis in an immunocompromised patient treated with intravitreal and systemic antibiotics while on rifabutin therapy for pulmonary tuberculosis (TB). Observations: A 63-year-old female from West Africa with a past medical history of HIV/AIDS, hepatitis B, and pulmonary TB presented with pain and acute vision loss in the left eye for two days. She was compliant with her treatment regimen for HIV and maintenance therapy for TB including rifabutin. Ocular examination revealed hypopyon uveitis in the left eye (OS). She was treated with broad spectrum systemic antimicrobials, topical prednisolone acetate, and intravitreal injections of vancomycin, ceftazidime, voriconazole, and ganciclovir, with resolution of hypopyon OS in 3 days. Aqueous sampling and systemic workup were unrevealing for causative infection. Two weeks later, she returned with a nearly identical presentation in the right eye (OD) with hypopyon uveitis and was again treated with intravitreal antibiotics. Anterior segment inflammation OD quickly improved after initiation of topical prednisolone acetate 1 % to reveal segmental retinal arteritis on fundus examination. As aqueous sampling was negative for infectious causes, she was diagnosed with presumed rifabutin associated-hypopyon uveitis in both eyes (OU) and segmental retinal arteritis OD, which has not been described previously with rifabutin use. Rifabutin was discontinued and there were no recurrences of uveitis over nine months of follow-up. Conclusions and importance/implications: Uveitis is an uncommon dose-related toxicity of rifabutin therapy. Segmental retinal arteritis (SRA) may be a rare finding when there is posterior segment involvement, especially in patients with concurrent TB infection. This report highlights a case of delayed bilateral hypopyon-uveitis and expands the presentation to include SRA. Patients treated with rifabutin should be counseled on signs and symptoms of uveitis. Development of rifabutin-associated uveitis may require medication discontinuation.

Effectiveness of Integrating Suicide Care in Primary Care : Secondary Analysis of a Stepped-Wedge, Cluster Randomized Implementation Trial.

BACKGROUND: Primary care encounters are common among patients at risk for suicide. OBJECTIVE: To evaluate the effectiveness of implementing population-based suicide care (SC) in primary care for suicide attempt prevention. DESIGN: Secondary analysis of a stepped-wedge, cluster randomized implementation trial. (ClinicalTrials.gov: NCT02675777). SETTING: 19 primary care practices within a large health care system in Washington State, randomly assigned launch dates. PATIENTS: Adult patients (aged ≥18 years) with primary care visits from January 2015 to July 2018. INTERVENTION: Practice facilitators, electronic medical record (EMR) clinical decision support, and performance monitoring supported implementation of depression screening, suicide risk assessment, and safety planning. MEASUREMENTS: Clinical practice and patient measures relied on EMR and insurance claims data to compare usual care (UC) and SC periods. Primary outcomes included documented safety planning after population-based screening and suicide risk assessment and suicide attempts or deaths (with self-harm intent) within 90 days of a visit. Mixed-effects logistic models regressed binary outcome indicators on UC versus SC, adjusted for randomization stratification and calendar time, accounting for repeated outcomes from the same site. Monthly outcome rates (percentage per 10 000 patients) were estimated by applying marginal standardization. RESULTS: During UC, 255 789 patients made 953 402 primary care visits and 228 255 patients made 615 511 visits during the SC period. The rate of safety planning was higher in the SC group than in the UC group (38.3 vs. 32.8 per 10 000 patients; rate difference, 5.5 [95% CI, 2.3 to 8.7]). Suicide attempts within 90 days were lower in the SC group than in the UC group (4.5 vs. 6.0 per 10 000 patients; rate difference, -1.5 [CI, -2.6 to -0.4]). LIMITATION: Suicide care was implemented in combination with care for depression and substance use. CONCLUSION: Implementation of population-based SC concurrent with a substance use program resulted in a 25% reduction in the suicide attempt rate in the 90 days after primary care visits. PRIMARY FUNDING SOURCE: National Institute of Mental Health.

Predicting adolescent psychopathology from early life factors: A machine learning tutorial.

Objective: The successful implementation and interpretation of machine learning (ML) models in epidemiological studies can be challenging without an extensive programming background. We provide a didactic example of machine learning for risk prediction in this study by determining whether early life factors could be useful for predicting adolescent psychopathology. Methods: In total, 9643 adolescents ages 9-10 from the Adolescent Brain and Cognitive Development (ABCD) Study were included in ML analysis to predict high Child Behavior Checklist (CBCL) scores (i.e., t-scores ≥ 60). ML models were constructed using a series of predictor combinations (prenatal, family history, sociodemographic) across 5 different algorithms. We assessed ML performance through sensitivity, specificity, F1-score, and area under the curve (AUC) metrics. Results: A total of 1267 adolescents (13.1 %) were found to have high CBCL scores. The best performing algorithms were elastic net and gradient boosted trees. The best performing elastic net models included prenatal and family history factors (Sensitivity 0.654, Specificity 0.713; AUC 0.742, F1-score 0.401) and prenatal, family, history, and sociodemographic factors (Sensitivity 0.668, Specificity 0.704; AUC 0.745, F1-score 0.402). Across all 5 ML algorithms, family history factors (e.g., either parent had nervous breakdowns, trouble holding jobs/fights/police encounters, and counseling for mental issues) and sociodemographic covariates (e.g., maternal age, child's sex, caregiver income and caregiver education) tended to be better predictors of adolescent psychopathology. The most important prenatal predictors were unplanned pregnancy, birth complications, and pregnancy complications. Conclusion: Our results suggest that inclusion of prenatal, family history, and sociodemographic factors in ML models can generate moderately accurate predictions of adolescent psychopathology. Issues associated with model overfitting, hyperparameter tuning, and system seed setting should be considered throughout model training, testing, and validation. Future early risk predictions models may improve with the inclusion of additional relevant covariates.

Use of ICD-10-CM Codes for Adverse Social Determinants of Health Across Health Systems.

OBJECTIVE: This study investigated ICD-10-CM codes for adverse social determinants of health (SDoH) across 12 U.S. health systems by using data from multiple health care encounter types for diverse patients covered by multiple payers. METHODS: The authors described documentation of 11 SDoH ICD-10-CM code categories (e.g., educational problems or social environmental problems) between 2016 and 2021; assessed changes over time by using chi-square tests for trend in proportions; compared documentation in 2021 by gender, age, race-ethnicity, and site with chi-square tests; and compared all patients' mental health outcomes in 2021 with those of patients with documented SDoH ICD-10-CM codes by using exact binomial tests and one-proportion z tests. RESULTS: Documentation of any SDoH ICD-10-CM code significantly increased, from 1.7% of patients in 2016 to 2.7% in 2021, as did that for all SDoH categories except educational problems. Documentation was often more prevalent among female patients and those of other or unknown gender than among male patients and among American Indian or Alaska Native, Black or African American, and Hispanic individuals than among those belonging to other race-ethnicity categories. More educational problems were documented for younger patients, and more social environmental problems were documented for older patients. Psychiatric diagnoses and emergency department visits and hospitalizations related to mental health were more common among patients with documented SDoH codes. CONCLUSIONS: SDoH ICD-10-CM code documentation was infrequent and differed by population subgroup. Differences may reflect documentation practices or true SDoH prevalence variation. Standardized SDoH documentation methods are needed in health care settings.

The prognostic impact of tumor deposits in colorectal cancer: More than just N1c.

BACKGROUND: The identification of tumor deposits (TD) currently plays a limited role in staging for colorectal cancer (CRC) aside from N1c lymph node designation. The objective of this study was to determine the prognostic impact, beyond American Joint Committee on Cancer N1c designation, of TDs among patients with primary CRC. METHODS: Patients who had resected stage I-III primary CRC diagnosed between 2010 and 2019 were identified from the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Cancer-specific survival (CSS) stratified by TD status and lymph node (N) status was calculated using the Kaplan-Meier method and multivariable Cox proportional hazards regression analyses. RESULTS: In total, 147,783 patients with primary CRC were identified. TDs were present in 15,444 patients (10.5%). The presence of TDs was significantly associated with adverse tumor characteristics, including advanced pathologic stage, nodal status, and metastasis status. The presence of TDs was associated with worse CSS (hazard ratio [HR], 3.12; 95% confidence interval [CI], 3.02-3.22), as it was for each given N category (e.g., N2a and TD-negative [HR, 2.50; 95% CI, 2.37-2.64] vs. N2a and TD-positive [HR, 3.75; 95% CI, 3.49-4.03]). The presence of multiple TDs was also associated with decreased CSS for each given N category compared with a single TD (e.g. N2a with one TD [HR, 3.09; 95% CI, 2.65-3.61] vs. N2a with two or more TDs [HR, 4.32; 95% CI, 3.87-4.82]). CONCLUSIONS: TDs were identified as an independent predictor of a worse outcome in patients with CRC. The presence of TDs confers distinctly different CSS and provides important prognostic information among patients with CRC and warrants further investigation as a unique variable in future iterations of CRC staging.

3-generation family histories of mental, neurologic, cardiometabolic, birth defect, asthma, allergy, and autoimmune conditions associated with autism: An open-source catalog of findings.

The relatively few conditions and family member types (e.g., sibling, parent) considered in investigations of family health history in autism spectrum disorder (ASD, or autism) limits understanding of the role of family history in autism etiology. For more comprehensive understanding and hypothesis-generation, we produced an open-source catalog of autism associations with family histories of mental, neurologic, cardiometabolic, birth defect, asthma, allergy, and autoimmune conditions. All live births in Denmark, 1980-2012, of Denmark-born parents (1,697,231 births), and their 3-generation family members were followed through April 10, 2017 for each of 90 diagnoses (including autism), emigration or death. Adjusted hazard ratios (aHR) were estimated via Cox regression for each diagnosis-family member type combination, adjusting for birth year, sex, birth weight, gestational age, parental ages at birth, and number of family member types of index person; aHRs also calculated for sex-specific co-occurrence of each disorder. We obtained 6462 individual family history aHRS across autism overall (26,840 autistic persons; 1.6% of births), by sex, and considering intellectual disability (ID); and 350 individual co-occurrence aHRS. Results are cataloged in interactive heat maps and down-loadable data files: https://ncrr-au.shinyapps.io/asd-riskatlas/ and interactive graphic summaries: https://public.tableau.com/app/profile/diana.schendel/viz/ASDPlots_16918786403110/e-Figure5. While primarily for reference material or use in other studies (e.g., meta-analyses), results revealed considerable breadth and variation in magnitude of familial health history associations with autism by type of condition, family member type, sex of the family member, side of the family, sex of the index person, and ID status, indicative of diverse genetic, familial, and nongenetic autism etiologic pathways. Careful attention to sources of autism likelihood in family health history, aided by our open data resource, may accelerate understanding of factors underlying neurodiversity.

Large library docking identifies positive allosteric modulators of the calcium-sensing receptor.

Positive allosteric modulator (PAM) drugs enhance the activation of the calcium-sensing receptor (CaSR) and suppress parathyroid hormone (PTH) secretion. Unfortunately, these hyperparathyroidism-treating drugs can induce hypocalcemia and arrhythmias. Seeking improved modulators, we docked libraries of 2.7 million and 1.2 billion molecules against the CaSR structure. The billion-molecule docking found PAMs with a 2.7-fold higher hit rate than the million-molecule library, with hits up to 37-fold more potent. Structure-based optimization led to nanomolar leads. In ex vivo organ assays, one of these PAMs was 100-fold more potent than the standard of care, cinacalcet, and reduced serum PTH levels in mice without the hypocalcemia typical of CaSR drugs. As determined from cryo-electron microscopy structures, the PAMs identified here promote CaSR conformations that more closely resemble the activated state than those induced by the established drugs.

The Effects of Torso-Borne Loads on Functional Movement Patterns.

Functional movement patterns are an important aspect of everyday life, and a growing area of interest for determining the risk of injury and performance ability. Police, military, and fire personnel often carry torso-borne loads that increase the demands on the body while performing occupational tasks. The purpose of this study was to compare movement screen results in both a loaded and unloaded condition to identify potential effects that torso-borne body armor load carriage may have on tactical performance. This provided objective data on the effects that external loads may have on functional movement patterns. Twenty-four physically active participants (11 males, 13 females) volunteered and completed the Fusionetics™ Movement Efficiency Test (FMET) in two conditions: loaded (wearing a 13.5 kg tactical vest) and unloaded, in a counterbalanced order. Participants were video recorded performing these movements and scored later. The overall scores, on a scale of 0 to 100, showed a large, statistically significant decline in functional movement pattern quality from the unloaded to the loaded condition (12.6±7.3 points, p<.001, d=1.8). In the subscales, statistically significant declines (p<.001) were seen in the 2-leg squat (d=0.8), push-ups (d=1.1), shoulder movements (d=2.1), and trunk movements (d=0.9). There was no significant effect of load on the cervical movements or 1-leg squat. Overall, torso-borne body armor loading decreased functional movement pattern quality, suggesting the potential benefit of performing loaded movement screens on tactical athletes.

Emerging Hybrid Intracoronary Imaging Technologies and Their Applications in Clinical Practice and Research.

Intravascular ultrasound and optical coherence tomography are used with increasing frequency for the care of coronary patients and in research studies. These imaging tools can identify culprit lesions in acute coronary syndromes, assess coronary stenosis severity, guide percutaneous coronary intervention (PCI), and detect vulnerable plaques and patients. However, they have significant limitations that have stimulated the development of multimodality intracoronary imaging catheters, which provide improvements in assessing vessel wall pathology and guiding PCI. Prototypes combining 2 or even 3 imaging probes with complementary attributes have been developed, and several multimodality systems have already been used in patients, with near-infrared spectroscopy intravascular ultrasound-based studies showing promising results for the identification of high-risk plaques. Moreover, postmortem histology studies have documented that hybrid imaging catheters can enable more accurate characterization of plaque morphology than standalone imaging. This review describes the evolution in the field of hybrid intracoronary imaging; presents the available multimodality catheters; and discusses their potential role in PCI guidance, vulnerable plaque detection, and the assessment of endovascular devices and emerging pharmacotherapies targeting atherosclerosis.