Inaccurate statements and lies from public figures and political and government leaders have the power to exacerbate dangerous upheavals in our political, health care, and social environments. The ...widespread misinformation, inaccuracies, and lies about the COVID-19 pandemic (about the origin of the virus, the severity of illness, vaccination, and "cures," to name a few) illustrate the potentially disastrous consequences of false information. Academic medicine must recognize the dangers of such lies and inaccuracies, particularly those related to health, and must understand their sources in traditional and social media and how and why many in the public accept them. Academic health professionals have a unique responsibility to promote and defend the truth in medicine and science, help the public to understand the sources of inaccurate scientific information, and find ways to debunk falsehoods spread by politicians and media outlets. Inaccurate information and lies have threatened the health of the population, the function of health systems, and the training of the future health workforce. They must be combatted by truth telling through scholarly work, clinical activities, and educating health professions trainees at all levels. Academic medicine's institutions should also consider joining the communities they serve and their medical specialty organizations to engage in political advocacy whenever possible. Health professions journals have an important role in highlighting and clarifying important topics and sustaining conversations on them within the academic medicine community. Across all its missions and activities, academic medicine must do its best to combat today's poisonous misinformation, inaccuracies, and lies, and to enter the larger social and political struggles that will determine the health of society and the future.
Prior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate ...genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of these genes explicitly evaluated common variant hypotheses about schizophrenia. Our evaluation included a meta-analysis of the candidate gene literature, incorporation of the results of the largest genomic study yet published for schizophrenia, ratings from informed researchers who have published on these genes, and ratings from 24 schizophrenia geneticists. On the basis of current empirical evidence and mostly consensual assessments of informed opinion, it appears that the historical candidate gene literature did not yield clear insights into the genetic basis of schizophrenia. A likely reason why historical candidate gene studies did not achieve their primary aims is inadequate statistical power. However, the considerable efforts embodied in these early studies unquestionably set the stage for current successes in genomic approaches to schizophrenia.
By analyzing the exomes of 12,332 unrelated Swedish individuals, including 4,877 individuals affected with schizophrenia, in ways informed by exome sequences from 45,376 other individuals, we ...identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant among individuals with schizophrenia than among controls (P = 1.3 × 10
). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this elevation arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk.
Bipolar disorder (BD) is a common neuropsychiatric disorder characterized by chronic recurrent episodes of depression and mania. Despite evidence for high heritability of BD, little is known about ...its underlying pathophysiology. To develop new tools for investigating the molecular and cellular basis of BD, we applied a family-based paradigm to derive and characterize a set of 12 induced pluripotent stem cell (iPSC) lines from a quartet consisting of two BD-affected brothers and their two unaffected parents. Initially, no significant phenotypic differences were observed between iPSCs derived from the different family members. However, upon directed neural differentiation, we observed that CXCR4 (CXC chemokine receptor-4) expressing central nervous system (CNS) neural progenitor cells (NPCs) from both BD patients compared with their unaffected parents exhibited multiple phenotypic differences at the level of neurogenesis and expression of genes critical for neuroplasticity, including WNT pathway components and ion channel subunits. Treatment of the CXCR4(+) NPCs with a pharmacological inhibitor of glycogen synthase kinase 3, a known regulator of WNT signaling, was found to rescue a progenitor proliferation deficit in the BD patient NPCs. Taken together, these studies provide new cellular tools for dissecting the pathophysiology of BD and evidence for dysregulation of key pathways involved in neurodevelopment and neuroplasticity. Future generation of additional iPSCs following a family-based paradigm for modeling complex neuropsychiatric disorders in conjunction with in-depth phenotyping holds promise for providing insights into the pathophysiological substrates of BD and is likely to inform the development of targeted therapeutics for its treatment and ideally prevention.
The Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC) highlighted 81 single-nucleotide polymorphisms (SNPs) with moderate evidence for association to schizophrenia. After ...follow-up in independent samples, seven loci attained genome-wide significance (GWS), but multi-locus tests suggested some SNPs that did not do so represented true associations. We tested 78 of the 81 SNPs in 2640 individuals with a clinical diagnosis of schizophrenia attending a clozapine clinic (CLOZUK), 2504 cases with a research diagnosis of bipolar disorder, and 2878 controls. In CLOZUK, we obtained significant replication to the PGC-associated allele for no fewer than 37 (47%) of the SNPs, including many prior GWS major histocompatibility complex (MHC) SNPs as well as 3/6 non-MHC SNPs for which we had data that were reported as GWS by the PGC. After combining the new schizophrenia data with those of the PGC, variants at three loci (ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS in schizophrenia attained that level of support. In bipolar disorder, we also obtained significant evidence for association for 21% of the alleles that had been associated with schizophrenia in the PGC. Our study independently confirms association to three loci previously reported to be GWS in schizophrenia, and identifies the first GWS evidence in schizophrenia for a further three loci. Given the number of independent replications and the power of our sample, we estimate 98% (confidence interval (CI) 78-100%) of the original set of 78 SNPs represent true associations. We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder.
Schizophrenia is a highly polygenic brain disorder. The main hypothesis for disease etiology in schizophrenia primarily focuses on the role of dysfunctional synaptic transmission. Previous studies ...have therefore directed their investigations toward the role of neuronal dysfunction. However, recent studies have shown that apart from neurons, glial cells also play a major role in synaptic transmission. Therefore, we investigated the potential causal involvement of the 3 principle glial cell lineages in risk to schizophrenia. We performed a functional gene set analysis to test for the combined effects of genetic variants in glial type-specific genes for association with schizophrenia. We used genome-wide association data from the largest schizophrenia sample to date, including 13 689 cases and 18 226 healthy controls. Our results show that astrocyte and oligodendrocyte gene sets, but not microglia gene sets, are associated with an increased risk for schizophrenia. The astrocyte and oligodendrocyte findings are related to astrocyte signaling at the synapse, myelin membrane integrity, glial development, and epigenetic control. Together, these results show that genetic alterations underlying specific glial cell type functions increase susceptibility to schizophrenia and provide evidence that the neuronal hypothesis of schizophrenia should be extended to include the role of glia.
COVID-19 has disrupted every aspect of the U.S. health care and health professions education systems, creating anxiety, suffering, and chaos and exposing many of the flaws in the nation’s public ...health, medical education, and political systems. The pandemic has starkly revealed the need for a better public health infrastructure and a health system with incentives for population health and prevention of disease as well as outstanding personalized curative health. It has also provided opportunities for innovations in health care and has inspired courageous actions of residents, who have responded to the needs of their patients despite risk to themselves. In this Invited Commentary, the author shares lessons he learned from 3 earlier disasters and discusses needed changes in medical education, health care, and health policy that the COVID-19 pandemic has revealed. He encourages health professions educators to use the experiences of this pandemic to reexamine the current curricular emphasis on the bioscientific model of health and to broaden the educational approach to incorporate the behavioral, social, and environmental factors that influence health. Surveillance for disease, investment in disease and injury prevention, and disaster planning should be basic elements of health professions education. Incorporating innovations such as telemedicine, used under duress during the pandemic, could alter educational and clinical approaches to create something better for students, residents, and patients. He explains that journals such as Academic Medicine can provide rapid, curated, expert advice that can be an important counterweight to the misinformation that circulates during disasters. Such journals can also inform their readers about new training in skills needed to mitigate the ongoing effects of the disaster and prepare the workforce for future disasters.
Foreign body airway obstruction (FBAO) due to food can occur wherever people eat, including in hospitals. We characterized in-hospital FBAO incidents and their outcomes.
We searched the Japan Council ...for Quality Health Care nationwide in-hospital adverse events database for relevant events from 1,549 institutions. We included all patients with FBAO incidents due to food in the hospital from January 2010 to June 2021 and collected data on the characteristics, interventions, and outcomes. FBAO from non-food materials were excluded. Our primary outcomes were mortality and morbidity from FBAO incidents.
We identified 300 patients who had a FBAO incident from food. The most common age group was 80–89 years old (32.3%, n = 97/300). One-half (50.0%, n = 150/300) were witnessed events. Suction was the most common first intervention (31.3%, n = 94/300) and resulted in successful removal of foreign body in 17.0% of cases (n = 16/94). Back blows (16.0%, n = 48/300) and abdominal thrusts (8.1%, n = 24/300) were less frequently performed as the first intervention and the success rates were 10.4% (n = 5/48) and 20.8% (n = 5/24), respectively. About one‐third of the patients (31%, n = 93/300) died and 26.7% (n = 80/300) had a high potential of residual disability from these incidents.
FBAO from food in the hospital is an uncommon but life-threatening event. The majority of patients who suffered from in-hospital FBAO incidents did not receive effective interventions initially and many of them died or suffered residual disability.
Bipolar disorder and schizophrenia are two often severe disorders with high heritabilities. Recent studies have demonstrated a large overlap of genetic risk loci between these disorders but ...diagnostic and molecular distinctions still remain. Here, we perform a combined genome-wide association study (GWAS) of 19 779 bipolar disorder (BP) and schizophrenia (SCZ) cases versus 19 423 controls, in addition to a direct comparison GWAS of 7129 SCZ cases versus 9252 BP cases. In our case-control analysis, we identify five previously identified regions reaching genome-wide significance (CACNA1C, IFI44L, MHC, TRANK1 and MAD1L1) and a novel locus near PIK3C2A. We create a polygenic risk score that is significantly different between BP and SCZ and show a significant correlation between a BP polygenic risk score and the clinical dimension of mania in SCZ patients. Our results indicate that first, combining diseases with similar genetic risk profiles improves power to detect shared risk loci and second, that future direct comparisons of BP and SCZ are likely to identify loci with significant differential effects. Identifying these loci should aid in the fundamental understanding of how these diseases differ biologically. These findings also indicate that combining clinical symptom dimensions and polygenic signatures could provide additional information that may someday be used clinically.
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