Foreword: Urban Bioethics

On February 26, 1997, the Fordham University School of Law hosted the Sixth Annual Stein Center Symposium on Contemporary Urban Challenges, entitled Urban Bioethics: A Symposium on Health Care, Poverty, and Autonomy. The Foreword introduces Articles in this Symposium issue and discusses two central themes of the various Articles: socioeconomic framing of bioethical and healthcare issues, and the challenge of the moral consensus

From regional pulse vaccination to global disease eradication: insights from a mathematical model of Poliomyelitis

Mass-vaccination campaigns are an important strategy in the global fight against poliomyelitis and measles. The large-scale logistics required for these mass immunisation campaigns magnifies the need for research into the effectiveness and optimal deployment of pulse vaccination. In order to better understand this control strategy, we propose a mathematical model accounting for the disease dynamics in connected regions, incorporating seasonality, environmental reservoirs and independent periodic pulse vaccination schedules in each region. The effective reproduction number, $R_e$, is defined and proved to be a global threshold for persistence of the disease. Analytical and numerical calculations show the importance of synchronising the pulse vaccinations in connected regions and the timing of the pulses with respect to the pathogen circulation seasonality. Our results indicate that it may be crucial for mass-vaccination programs, such as national immunisation days, to be synchronised across different regions. In addition, simulations show that a migration imbalance can increase $R_e$ and alter how pulse vaccination should be optimally distributed among the patches, similar to results found with constant-rate vaccination. Furthermore, contrary to the case of constant-rate vaccination, the fraction of environmental transmission affects the value of $R_e$ when pulse vaccination is present.Comment: Added section 6.1, made other revisions, changed titl

Striatal vs extrastriatal dopamine D2 receptors in antipsychotic response - a double-blind PET study in schizophrenia

Blockade of dopamine D2 receptors remains a common feature of all antipsychotics. It has been hypothesized that the extrastriatal (cortical, thalamic) dopamine D2 receptors may be more critical to antipsychotic response than the striatal dopamine D2 receptors. This is the first double-blind controlled study to examine the relationship between striatal and extrastriatal D2 occupancy and clinical effects. Fourteen patients with recent onset psychosis were assigned to low or high doses of risperidone (1 mg vs 4 mg/day) or olanzapine (2.5 mg vs 15 mg/day) in order to achieve a broad range of D2 occupancy levels across subjects. Clinical response, side effects, striatal ([11C]-raclopride-positron emission tomography (PET)), and extrastriatal ([11C]-FLB 457-PET) D2 receptors were evaluated after treatment. The measured D2 occupancies ranged from 50 to 92% in striatal and 4 to 95% in the different extrastriatal (frontal, temporal, thalamic) regions. Striatal and extrastriatal occupancies were correlated with dose, drug plasma levels, and with each other. Striatal D2 occupancy predicted response in positive psychotic symptoms (r=0.62, p=0.01), but not for negative symptoms (r=0.2, p=0.5). Extrastriatal D2 occupancy did not predict response in positive or negative symptoms. The two subjects who experienced motor side effects had the highest striatal occupancies in the cohort. Striatal D2 blockade predicted antipsychotic response better than frontal, temporal, and thalamic occupancy. These results, when combined with the preclinical data implicating the mesolimbic striatum in antipsychotic response, suggest that dopamine D2 blockade within specific regions of the striatum may be most critical for ameliorating psychosis in schizophrenia.peer-reviewe

Association of Abnormal Semantic Processing with Delusion-like Ideation in Frequent Cannabis Users: An Electrophysiological Study

Rationale Frequent cannabis use is a risk marker for schizophrenia and delusions, but the neurocognitive mechanisms of this relationship remain unclear. Objectives We sought evidence that cannabis users have deficits in processing relationships between meaningful stimuli, similar to abnormalities reported in schizophrenia, and that these deficits are associated with delusion-like ideation. We used the N400 event-related brain potential (ERP) waveform as a neurophysiological probe of activation of concepts in semantic memory. We hypothesized that cannabis users would exhibit larger (more negative) than normal N400 amplitudes in response to stimuli meaningfully related to a preceding prime – reflecting deficient activation of concepts related to the prime. We further hypothesized that the magnitude of this abnormality would correlate with severity of delusion-like ideation. Methods We recorded ERPs in 24 frequent cannabis users and 24 non-using comparison participants, who viewed prime words followed by targets which were either words related or unrelated to the prime, or pronounceable nonwords. Participants’ task was to indicate whether the target was a word. Delusion-like ideation was measured via the Schizotypal Personality Questionnaire. Results Contrary to our hypothesis, cannabis users exhibited smaller than normal N400s to both related and unrelated targets. These abnormalities correlated with delusion-like ideation in cannabis users only. Conclusions The results are consistent with a generalized abnormality of activation within semantic memory neural networks in cannabis users. Further research is needed to investigate whether such an abnormality plays a role in development of delusion-like ideation in cannabis users

Modeling the mental health service utilization decisions of university undergraduates: A discrete choice conjoint experiment

Objective: We modeled design factors influencing the intent to use a university mental health service. Participants: Between November 2012 and October 2014, 909 undergraduates participated. Method: Using a discrete choice experiment, participants chose between hypothetical campus mental health services. Results: Latent class analysis identified three segments. A Psychological/Psychiatric Service segment (45.5%) was most likely to contact campus health services delivered by psychologists or psychiatrists. An Alternative Service segment (39.3%) preferred to talk to peer-counselors who had experienced mental health problems. A Hesitant segment (15.2%) reported greater distress but seemed less intent on seeking help. They preferred services delivered by psychologists or psychiatrists. Simulations predicted that, rather than waiting for standard counseling, the Alternative Service segment would prefer immediate access to E-Mental health. The Usual Care and Hesitant segments would wait 6 months for standard counseling. Conclusions: E-Mental Health options could engage students who may not wait for standard services.This project was supported by the Jack Laidlaw Chair in Patient-Centered Health Care and a grant from the Canadian Health Services Research Foundation

Hybrid Neurons in a MicroRNA Mutant Are Putative Evolutionary Intermediates in Insect CO_2 Sensory Systems

Carbon dioxide (CO_2) elicits different olfactory behaviors across species. In Drosophila, neurons that detect CO_2 are located in the antenna, form connections in a ventral glomerulus in the antennal lobe, and mediate avoidance. By contrast, in the mosquito these neurons are in the maxillary palps (MPs), connect to medial sites, and promote attraction. We found in Drosophila that loss of a microRNA, miR-279, leads to formation of CO_2 neurons in the MPs. miR-279 acts through down-regulation of the transcription factor Nerfin-1. The ectopic neurons are hybrid cells. They express CO_2 receptors and form connections characteristic of CO_2 neurons, while exhibiting wiring and receptor characteristics of MP olfactory receptor neurons (ORNs). We propose that this hybrid ORN reveals a cellular intermediate in the evolution of species-specific behaviors elicited by CO_2

Insight into the Regulation of Glycan Synthesis in Drosophila Chaoptin Based on Mass Spectrometry

BACKGROUND: A variety of N-glycans attached to protein are known to involve in many important biological functions. Endoplasmic reticulum (ER) and Golgi localized enzymes are responsible to this template-independent glycan synthesis resulting glycoforms at each asparagine residues. The regulation mechanism such glycan synthesis remains largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: In order to investigate the relationship between glycan structure and protein conformation, we analyzed a glycoprotein of Drosophila melanogaster, chaoptin (Chp), which is localized in photoreceptor cells and is bound to the cell membrane via a glycosylphosphatidylinositol anchor. Detailed analysis based on mass spectrometry revealed the presence of 13 N-glycosylation sites and the composition of the glycoform at each site. The synthetic pathway of glycans was speculated from the observed glycan structures and the composition at each N-glycosylation site, where the presence of novel routes were suggested. The distribution of glycoforms on a Chp polypeptide suggested that various processing enzymes act on the exterior of Chp in the Golgi apparatus, although virtually no enzyme can gain access to the interior of the horseshoe-shaped scaffold, hence explaining the presence of longer glycans within the interior. Furthermore, analysis of Chp from a mutant (RNAi against dolichyl-phosphate alpha-d-mannosyltransferase), which affects N-glycan synthesis in the ER, revealed that truncated glycan structures were processed. As a result, the distribution of glycoforms was affected for the high-mannose-type glycans only, whereas other types of glycans remained similar to those observed in the control and wild-type. CONCLUSIONS/SIGNIFICANCE: These results indicate that glycan processing depends largely on the backbone structure of the parent polypeptide. The information we obtained can be applied to other members of the LRR family of proteins

Answering real-world clinical questions using large language model based systems

Evidence to guide healthcare decisions is often limited by a lack of relevant and trustworthy literature as well as difficulty in contextualizing existing research for a specific patient. Large language models (LLMs) could potentially address both challenges by either summarizing published literature or generating new studies based on real-world data (RWD). We evaluated the ability of five LLM-based systems in answering 50 clinical questions and had nine independent physicians review the responses for relevance, reliability, and actionability. As it stands, general-purpose LLMs (ChatGPT-4, Claude 3 Opus, Gemini Pro 1.5) rarely produced answers that were deemed relevant and evidence-based (2% - 10%). In contrast, retrieval augmented generation (RAG)-based and agentic LLM systems produced relevant and evidence-based answers for 24% (OpenEvidence) to 58% (ChatRWD) of questions. Only the agentic ChatRWD was able to answer novel questions compared to other LLMs (65% vs. 0-9%). These results suggest that while general-purpose LLMs should not be used as-is, a purpose-built system for evidence summarization based on RAG and one for generating novel evidence working synergistically would improve availability of pertinent evidence for patient care.Comment: 28 pages (2 figures, 3 tables) inclusive of 8 pages of supplemental materials (4 supplemental figures and 4 supplemental tables