Deficiency in Perlecan/HSPG2 During Bone Development Enhances Osteogenesis and Decreases Quality of Adult Bone in Mice

Perlecan/HSPG2 (Pln) is a large heparan sulfate proteoglycan abundant in the extracellular matrix of cartilage and the lacunocanalicular space of adult bones. Although Pln function during cartilage development is critical, evidenced by deficiency disorders including Schwartz–Jampel Syndrome and dyssegmental dysplasia Silverman-Handmaker type, little is known about its function in development of bone shape and quality. The purpose of this study was to understand the contribution of Pln to bone geometric and mechanical properties. We used hypomorph mutant mice that secrete negligible amount of Pln into skeletal tissues and analyzed their adult bone properties using micro-computed tomography and three-point-bending tests. Bone shortening and widening in Pln mutants was observed and could be attributed to loss of growth plate organization and accelerated osteogenesis that was reflected by elevated cortical thickness at older ages. This effect was more pronounced in Pln mutant females, indicating a sex-specific effect of Pln deficiency on bone geometry. Additionally, mutant females, and to a lesser extent mutant males, increased their elastic modulus and bone mineral densities to counteract changes in bone shape, but at the expense of increased brittleness. In summary, Pln deficiency alters cartilage matrix patterning and, as we now show, coordinately influences bone formation and calcification

Neuroanatomical and cellular degeneration associated with a social disorder characterized by new ritualistic belief systems in a TDP-C patient vs. a Pick patient

Frontotemporal dementia (FTD) is a spectrum of clinically and pathologically heterogenous neurodegenerative dementias. Clinical and anatomical variants of FTD have been described and associated with underlying frontotemporal lobar degeneration (FTLD) pathology, including tauopathies (FTLD-tau) or TDP-43 proteinopathies (FTLD-TDP). FTD patients with predominant degeneration of anterior temporal cortices often develop a language disorder of semantic knowledge loss and/or a social disorder often characterized by compulsive rituals and belief systems corresponding to predominant left or right hemisphere involvement, respectively. The neural substrates of these complex social disorders remain unclear. Here, we present a comparative imaging and postmortem study of two patients, one with FTLD-TDP (subtype C) and one with FTLD-tau (subtype Pick disease), who both developed new rigid belief systems. The FTLD-TDP patient developed a complex set of values centered on positivity and associated with specific physical and behavioral features of pigs, while the FTLD-tau patient developed compulsive, goal-directed behaviors related to general themes of positivity and spirituality. Neuroimaging showed left-predominant temporal atrophy in the FTLD-TDP patient and right-predominant frontotemporal atrophy in the FTLD-tau patient. Consistent with antemortem cortical atrophy, histopathologic examinations revealed severe loss of neurons and myelin predominantly in the anterior temporal lobes of both patients, but the FTLD-tau patient showed more bilateral, dorsolateral involvement featuring greater pathology and loss of projection neurons and deep white matter. These findings highlight that the regions within and connected to anterior temporal lobes may have differential vulnerability to distinct FTLD proteinopathies and serve important roles in human belief systems

Correction for Johansson et al., An open challenge to advance probabilistic forecasting for dengue epidemics.

Correction for “An open challenge to advance probabilistic forecasting for dengue epidemics,” by Michael A. Johansson, Karyn M. Apfeldorf, Scott Dobson, Jason Devita, Anna L. Buczak, Benjamin Baugher, Linda J. Moniz, Thomas Bagley, Steven M. Babin, Erhan Guven, Teresa K. Yamana, Jeffrey Shaman, Terry Moschou, Nick Lothian, Aaron Lane, Grant Osborne, Gao Jiang, Logan C. Brooks, David C. Farrow, Sangwon Hyun, Ryan J. Tibshirani, Roni Rosenfeld, Justin Lessler, Nicholas G. Reich, Derek A. T. Cummings, Stephen A. Lauer, Sean M. Moore, Hannah E. Clapham, Rachel Lowe, Trevor C. Bailey, Markel García-Díez, Marilia Sá Carvalho, Xavier Rodó, Tridip Sardar, Richard Paul, Evan L. Ray, Krzysztof Sakrejda, Alexandria C. Brown, Xi Meng, Osonde Osoba, Raffaele Vardavas, David Manheim, Melinda Moore, Dhananjai M. Rao, Travis C. Porco, Sarah Ackley, Fengchen Liu, Lee Worden, Matteo Convertino, Yang Liu, Abraham Reddy, Eloy Ortiz, Jorge Rivero, Humberto Brito, Alicia Juarrero, Leah R. Johnson, Robert B. Gramacy, Jeremy M. Cohen, Erin A. Mordecai, Courtney C. Murdock, Jason R. Rohr, Sadie J. Ryan, Anna M. Stewart-Ibarra, Daniel P. Weikel, Antarpreet Jutla, Rakibul Khan, Marissa Poultney, Rita R. Colwell, Brenda Rivera-García, Christopher M. Barker, Jesse E. Bell, Matthew Biggerstaff, David Swerdlow, Luis Mier-y-Teran-Romero, Brett M. Forshey, Juli Trtanj, Jason Asher, Matt Clay, Harold S. Margolis, Andrew M. Hebbeler, Dylan George, and Jean-Paul Chretien, which was first published November 11, 2019; 10.1073/pnas.1909865116. The authors note that the affiliation for Xavier Rodó should instead appear as Catalan Institution for Research and Advanced Studies (ICREA) and Climate and Health Program, Barcelona Institute for Global Health (ISGlobal). The corrected author and affiliation lines appear below. The online version has been corrected

An open challenge to advance probabilistic forecasting for dengue epidemics.

A wide range of research has promised new tools for forecasting infectious disease dynamics, but little of that research is currently being applied in practice, because tools do not address key public health needs, do not produce probabilistic forecasts, have not been evaluated on external data, or do not provide sufficient forecast skill to be useful. We developed an open collaborative forecasting challenge to assess probabilistic forecasts for seasonal epidemics of dengue, a major global public health problem. Sixteen teams used a variety of methods and data to generate forecasts for 3 epidemiological targets (peak incidence, the week of the peak, and total incidence) over 8 dengue seasons in Iquitos, Peru and San Juan, Puerto Rico. Forecast skill was highly variable across teams and targets. While numerous forecasts showed high skill for midseason situational awareness, early season skill was low, and skill was generally lowest for high incidence seasons, those for which forecasts would be most valuable. A comparison of modeling approaches revealed that average forecast skill was lower for models including biologically meaningful data and mechanisms and that both multimodel and multiteam ensemble forecasts consistently outperformed individual model forecasts. Leveraging these insights, data, and the forecasting framework will be critical to improve forecast skill and the application of forecasts in real time for epidemic preparedness and response. Moreover, key components of this project-integration with public health needs, a common forecasting framework, shared and standardized data, and open participation-can help advance infectious disease forecasting beyond dengue

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Development of text messages for primary prevention of cardiovascular disease in persons with HIV

ObjectivePersons with HIV (PWH) have increased risk for atherosclerotic cardiovascular disease (CVD). Despite this increased risk, perceived cardiovascular risk among PWH is low, and interventions that are known to be beneficial in the general population, such as statins, have low uptake in this population. We sought to develop a bank of text messages about (1) the association between HIV and CVD and (2) advice on reducing cardiovascular risk.MethodsWe developed an initial bank of 162 messages. We solicited feedback from 29 PWH recruited from outpatient clinics providing HIV care at a large urban tertiary medical center and a public hospital in San Francisco, California. Participants reviewed 7-10 messages each and rated message usefulness, readability, and potential impact on behavior on a scale from 1 (least) to 5 (most). We also collected open-ended feedback on the messages and data on preferences about message timing.ResultsThe average score for the messages was 4.4/5 for usefulness, 4.4/5 for readability, and 4.0/5 for potential impact on behavior. The text messages were iteratively revised based on participant feedback, and lowest-rated messages were removed from the message bank. The final message bank included 116 messages on diet (30.2%), physical activity (24.8%), tobacco (11.2%), the association between HIV and cardiovascular disease (9.5%), general heart health (6.9%), cholesterol (5.2%), blood pressure (4.3%), blood sugar (2.6%), sleep (2.6%), and weight (2.6%).ConclusionWe describe an approach for developing educational text messages on primary prevention of cardiovascular disease among PWH

A Quantitative Framework to Evaluate Modeling of Cortical Development by Neural Stem Cells

Neural stem cells have been adopted to model a wide range of neuropsychiatric conditions in vitro. However, how well such models correspond to in vivo brain has not been evaluated in an unbiased, comprehensive manner. We used transcriptomic analyses to compare in vitro systems to developing human fetal brain and observed strong conservation of in vivo gene expression and network architecture in differentiating primary human neural progenitor cells (phNPCs). Conserved modules are enriched in genes associated with ASD, supporting the utility of phNPCs for studying neuropsychiatric disease. We also developed and validated a machine learning approach called CoNTExT that identifies the developmental maturity and regional identity of in vitro models. We observed strong differences between in vitro models, including hiPSC-derived neural progenitors from multiple laboratories. This work provides a systems biology framework for evaluating in vitro systems and supports their value in studying the molecular mechanisms of human neurodevelopmental disease

Data_Sheet_1_Neuroanatomical and cellular degeneration associated with a social disorder characterized by new ritualistic belief systems in a TDP-C patient vs. a Pick patient.docx

Frontotemporal dementia (FTD) is a spectrum of clinically and pathologically heterogenous neurodegenerative dementias. Clinical and anatomical variants of FTD have been described and associated with underlying frontotemporal lobar degeneration (FTLD) pathology, including tauopathies (FTLD-tau) or TDP-43 proteinopathies (FTLD-TDP). FTD patients with predominant degeneration of anterior temporal cortices often develop a language disorder of semantic knowledge loss and/or a social disorder often characterized by compulsive rituals and belief systems corresponding to predominant left or right hemisphere involvement, respectively. The neural substrates of these complex social disorders remain unclear. Here, we present a comparative imaging and postmortem study of two patients, one with FTLD-TDP (subtype C) and one with FTLD-tau (subtype Pick disease), who both developed new rigid belief systems. The FTLD-TDP patient developed a complex set of values centered on positivity and associated with specific physical and behavioral features of pigs, while the FTLD-tau patient developed compulsive, goal-directed behaviors related to general themes of positivity and spirituality. Neuroimaging showed left-predominant temporal atrophy in the FTLD-TDP patient and right-predominant frontotemporal atrophy in the FTLD-tau patient. Consistent with antemortem cortical atrophy, histopathologic examinations revealed severe loss of neurons and myelin predominantly in the anterior temporal lobes of both patients, but the FTLD-tau patient showed more bilateral, dorsolateral involvement featuring greater pathology and loss of projection neurons and deep white matter. These findings highlight that the regions within and connected to anterior temporal lobes may have differential vulnerability to distinct FTLD proteinopathies and serve important roles in human belief systems.</p