Bioregulatory systems medicine: an innovative approach to integrating the science of molecular networks, inflammation, and systems biology with the patient\u27s autoregulatory capacity?

Bioregulatory systems medicine (BrSM) is a paradigm that aims to advance current medical practices. The basic scientific and clinical tenets of this approach embrace an interconnected picture of human health, supported largely by recent advances in systems biology and genomics, and focus on the implications of multi-scale interconnectivity for improving therapeutic approaches to disease. This article introduces the formal incorporation of these scientific and clinical elements into a cohesive theoretical model of the BrSM approach. The authors review this integrated body of knowledge and discuss how the emergent conceptual model offers the medical field a new avenue for extending the armamentarium of current treatment and healthcare, with the ultimate goal of improving population health

Old stones' song: Use-wear experiments and analysis of the Oldowan quartz and quartzite assemblage from Kanjera South (Kenya)

Evidence of Oldowan tools by w2.6 million years ago (Ma) may signal a major adaptive shift in hominin evolution. While tool-dependent butchery of large mammals was important by at least 2.0 Ma, the use of artifacts for tasks other than faunal processing has been difficult to diagnose. Here we report on use-wear analysis ofw2.0 Ma quartz and quartzite artifacts from Kanjera South, Kenya. A use-wear framework that links processing of specific materials and tool motions to their resultant use-wear patterns was developed. A blind test was then carried out to assess and improve the efficacy of this experimental use-wear framework, which was then applied to the analysis of 62 Oldowan artifacts from Kanjera South. Usewear on a total of 23 artifact edges was attributed to the processing of specific materials. Use-wear on seven edges (30%) was attributed to animal tissue processing,corroborating zooarchaeological evidence for butchery at the site. Use-wear on 16 edges (70%)was attributed to the processing of plant tissues, including wood, grit-covered plant tissues that we interpret asunderground storage organs (USOs), and stems of grass or sedges. These results expand our knowledge of the suite of behaviours carried out in the vicinity of Kanjera South to include the processing of materials that would be ‘invisible’ using standard archaeological methods. Wood cutting and scraping may represent the production and/or maintenance of wooden tools. Use-wear related to USO processing extends the archaeological evidence for hominin acquisition and consumption of this resource by over 1.5 Ma. Cutting of grasses, sedges or reeds may be related to a subsistence task (e.g., grass seed harvesting, cutting out papyrus culm for consumption) and/or a non-subsistence related task (e.g., production of ‘twine,’ simple carrying devices, or bedding). These results highlight the adaptive significance of lithic technology for hominins at Kanjera

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

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

Bioregulatory Systems Medicine: An Innovative Approach to Integrating the Science of Molecular Networks, Inflammation and Systems Biology with the Patient’s Autoregulatory Capacity?

Bioregulatory systems medicine is a paradigm that aims to advance current medical practices. The basic scientific and clinical tenets of this approach embrace an interconnected picture of human health, supported largely by recent advances in systems biology and genomics, and focuses on the implications of multi-scale interconnectivity for improving therapeutic approaches to disease. This article introduces the formal incorporation of these scientific and clinical elements into a cohesive theoretical model of the bioregulatory systems medicine approach. The authors review this integrated body of knowledge and discuss how the emergent conceptual model offers the medical field a new avenue for extending the armamentarium of current treatment and healthcare, with the ultimate goal of improving population health

What Percentage of Americans Have Ever Had a Family Member Incarcerated?: Evidence from the Family History of Incarceration Survey (FamHIS)

What percentage of Americans have ever had a family member incarcerated? To answer this question, we designed the Family History of Incarceration Survey (FamHIS). The survey was administered in the summer of 2018 by NORC at the University of Chicago using their AmeriSpeak Panel. It was funded by FWD.us, which released a separate report using the data. The data show that 45 percent of Americans have ever had an immediate family member incarcerated. The incarceration of an immediate family member was most prevalent for blacks (63 percent) but common for whites (42 percent) and Hispanics (48 percent) as well. College graduates had a lower risk of having a family member incarcerated, but the risk for black college graduates was comparatively high. The most common form of family member incarceration was the incarceration of a sibling

A Longitudinal Investigation of Internalized Stigma, Constrained Disclosure, and Quality of Life Across 12 Weeks in Lung Cancer Patients on Active Oncologic Treatment

IntroductionInternalized lung cancer stigma (i.e., feelings of regret, shame, and self-blame about one's lung cancer) is related to poorer psychological outcomes. Less is known about how internalized stigma relates to physical and functional outcomes or how constrained disclosure (i.e., avoidance of or discomfort about disclosing one's lung cancer status to others) relates to well-being. Furthermore, no study has examined whether internalized stigma and constrained disclosure predict changes in well-being for lung cancer patients. This longitudinal study characterized relationships of internalized stigma and constrained disclosure with emotional and physical/functional outcomes.MethodsParticipants (N = 101, 52.4% male, 63.4% currently/formerly smoked) were lung cancer patients on active medical treatment who completed questionnaires on stigma and well-being at study entry and at 6- and 12-week follow-up. Multivariable linear regressions characterized relationships of internalized stigma and constrained disclosure with emotional and physical/functional well-being at study entry and across time.ResultsParticipants who currently or formerly smoked reported higher levels of internalized stigma (but not constrained disclosure), compared to never smokers (p < 0.001). Higher internalized stigma and constrained disclosure were uniquely associated with poorer emotional and physical/functional well-being at study entry (all p < 0.05), beyond sociodemographic characteristics, time elapsed since diagnosis, and smoking status. Higher internalized stigma predicted significant declines in emotional well-being across 6 and 12 weeks (all p < 0.01) and declines in physical/functional well-being across 6 weeks (p < 0.05).ConclusionsInternalized lung cancer stigma and constrained disclosure relate to emotional and physical/functional maladjustment. Findings carry implications for provider- and patient-focused interventions to reduce internalized stigma and promote well-being

A phase II study of continuous oral mTOR inhibitor everolimus for recurrent, radiographic-progressive neurofibromatosis type 1–associated pediatric low-grade glioma: a Neurofibromatosis Clinical Trials Consortium study

BackgroundActivation of the mammalian target of rapamycin (mTOR) pathway is observed in neurofibromatosis type 1 (NF1) associated low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population. We evaluate the efficacy of the orally administered mTOR inhibitor everolimus for radiographically progressive NF1-associated pediatric LGGs.MethodsChildren with radiologic-progressive, NF1-associated LGG and prior treatment with a carboplatin-containing chemotherapy were prospectively enrolled on this phase II clinical trial to receive daily everolimus. Whole blood was analyzed for everolimus and markers of phosphatidylinositol-3 kinase (PI3K)/mTOR pathway inhibition. Serial MRIs were obtained during treatment. The primary endpoint was progression-free survival at 48 weeks.ResultsTwenty-three participants (median age, 9.4 y; range, 3.2-21.6 y) were enrolled. All participants were initially evaluable for response; 1 patient was removed from study after development of a malignant peripheral nerve sheath tumor. Fifteen of 22 participants (68%) demonstrated a response, defined as either shrinkage (1 complete response, 2 partial response) or arrest of tumor growth (12 stable disease). Of these, 10/15 remained free of progression (median follow-up, 33 mo). All remaining 22 participants were alive at completion of therapy. Treatment was well tolerated; no patient discontinued therapy due to toxicity. Pharmacokinetic parameters and pre-dose concentrations showed substantial between-subject variability. PI3K/mTOR pathway inhibition markers demonstrating blood mononuclear cell mTOR pathway inactivation was achieved in most participants.ConclusionIndividuals with recurrent/progressive NF1-associated LGG demonstrate significant disease stability/shrinkage during treatment with oral everolimus with a well-tolerated toxicity profile. Everolimus is well suited for future consideration as upfront or combination therapy in this patient population