The neurodegenerative effects of Parkinson's disease (PD) are marked by a selective loss of dopaminergic (DA) neurons. Epidemiological studies suggest that chronic exposure to the pesticide paraquat may increase the risk for PD and DA cell loss. However, combined exposure with additional fungicide(s) including maneb and/or ziram may be required for pathogenesis. To explore potential pathogenic mechanisms, we have developed a Drosophila model of chronic paraquat exposure. We find that while chronic paraquat exposure alone decreased organismal survival and motor function, combined chronic exposure to both paraquat and maneb was required for DA cell death in the fly. To initiate mechanistic studies of this interaction, we used additional genetic reagents to target the ubiquitin proteasome system, which has been implicated in some rare familial forms of PD and the toxic effects of ziram. Genetic inhibition of E1 ubiquitin ligase, but not the proteasome itself, increased DA cell death in combination with maneb but not paraquat. These studies establish a model for long-term exposure to multiple pesticides, and support the idea that pesticide interactions relevant to PD may involve inhibition of protein ubiquitination.

BACKGROUND: While insurance is integral for accessing healthcare in the US, coverage alone may not ensure access, especially for those publicly insured. Access barriers for Medicaid-insured patients are rooted in social drivers of health, insurance complexities in the setting of managed care plans, and federal- and state-level policies. Elucidating barriers at the health system level may reveal opportunities for sustainable solutions. METHODS: To understand barriers to ambulatory care access for patients with Medi-Cal (Californias Medicaid program) and identify improvement opportunities, we performed a qualitative study using semi-structured interviews of a referred sample of clinicians and administrative staff members experienced with clinical patient encounters and/or completion of referral processes for patients with Medi-Cal (n = 19) at a large academic medical center. The interview guide covered the four process steps to accessing care within the health system: (1) scheduling, (2) referral and authorization, (3) contracting, and (4) the clinical encounter. We transcribed and inductively coded the interviews, then organized themes across the four steps to identify perceptions of barriers to access and improvement opportunities for ambulatory care for patients with Medi-Cal. RESULTS: Clinicians and administrative staff members at a large academic medical center revealed barriers to ambulatory care access for Medi-Cal insured patients, including lack of awareness of system-level policy, complexities surrounding insurance contracting, limited resources for social support, and poor dissemination of information to patients. Particularly, interviews revealed how managed Medi-Cal impacts academic health systems through additional time and effort by frontline staff to facilitate patient access compared to fee-for-service Medi-Cal. Interviewees reported that this resulted in patient care delays, suboptimal care coordination, and care fragmentation. CONCLUSIONS: Our findings highlight gaps in system-level policy, inconsistencies in pursuing insurance authorizations, limited resources for scheduling and social work support, and poor dissemination of information to and between providers and patients, which limit access to care at an academic medical center for Medi-Cal insured patients. Many interviewees additionally shared the moral injury that they experienced as they witnessed patient care delays in the absence of system-level structures to address these barriers. Reform at the state, insurance organization, and institutional levels is necessary to form solutions within Medi-Cal innovation efforts.

BACKGROUND: Ambulatory access to academic medical centers (AMCs) for patients insured with Medi-Cal (i.e., Medicaid in California) is understudied, particularly among the 85% of beneficiaries enrolled in managed care plans. As more AMCs develop partnerships with these plans, data on patient experiences of access to care and quality are needed to guide patient-centered improvements in care delivery. METHODS: The authors conducted semi-structured, qualitative interviews with Medi-Cal-insured patients with initial visits at a large, urban AMC during 2022. Participant recruitment was informed by a database of ambulatory Medi-Cal encounters. The interview guide covered Medi-Cal enrollment, scheduling, and visit experience. Interviews were transcribed and inductively coded, then organized into themes across four domains: access, affordability, patient-provider interactions, and continuity. RESULTS: Twenty participant interviews were completed (55% female, 85% English speaking, 80% self-identified minority or other race, and 30% Hispanic or Latino) with primary and/or specialty care visits. Within the access domain, participants reported delays with Medi-Cal enrollment and access to specialist care or testing, though appointment scheduling was reported to be easy. Affordability concerns included out-of-pocket medical and parking costs, and missed income when patients or families skipped work to facilitate care coordination. Participants considered clear, bilateral communication with providers fundamental to positive patient-provider interactions. Some participants perceived discrimination by providers based on their insurance status. Participants valued continuity, but experienced frustration arising from frequent and unexpected health plan changes that disrupted care with their established AMC providers. CONCLUSIONS: The missions of AMCs typically focus on clinical care, education, research, and equity. However, reports from Medi-Cal insured patients receiving care at AMCs highlight their stress and confusion related to inconsistent provider access, uncompensated costs, variability in perceptions of quality, and fragmented care. Recommendations based upon patient-reported concerns suggest opportunities for AMC health system-level improvements that are compatible with AMC missions.

The retinoid X receptor α (RXRα), a key nuclear receptor in metabolic processes, is downregulated during host antiviral response. However, the roles of RXRα in host antiviral response are unknown. Here we show that RXRα overexpression or ligand activation increases host susceptibility to viral infections in vitro and in vivo, while Rxra-/- or antagonist treatment reduces infection by the same viruses. Consistent with these functional studies, ligand activation of RXR inhibits the expression of antiviral genes including type I interferon (IFN) and Rxra-/- macrophages produce more IFNβ than WT macrophages in response to polyI:C stimulation. Further results indicate that ligand activation of RXR suppresses the nuclear translocation of β-catenin, a co-activator of IFNβ enhanceosome. Thus, our studies have uncovered a novel RXR-dependent innate immune regulatory pathway, suggesting that the downregulation of RXR expression or RXR antagonist treatment benefits host antiviral response, whereas RXR agonist treatment may increase the risk of viral infections.

Despite the development of next-generation antiandrogens, metastatic castration-resistant prostate cancer (mCRPC) remains incurable. Here, we describe a unique semisynthetic bispecific antibody that uses site-specific unnatural amino acid conjugation to combine the potency of a T cell-recruiting anti-CD3 antibody with the specificity of an imaging ligand (DUPA) for prostate-specific membrane antigen. This format enabled optimization of structure and function to produce a candidate (CCW702) with specific, potent in vitro cytotoxicity and improved stability compared with a bispecific single-chain variable fragment format. In vivo, CCW702 eliminated C4-2 xenografts with as few as three weekly subcutaneous doses and prevented growth of PCSD1 patient-derived xenograft tumors in mice. In cynomolgus monkeys, CCW702 was well tolerated up to 34.1 mg/kg per dose, with near-complete subcutaneous bioavailability and a PK profile supporting testing of a weekly dosing regimen in patients. CCW702 is being evaluated in a first in-human clinical trial for men with mCRPC who had progressed on prior therapies (NCT04077021).

The recent stall in the global reduction of malaria deaths has made the development of a highly effective vaccine essential. A major challenge to developing an efficacious vaccine is the extensive diversity of Plasmodium falciparum antigens. While genetic diversity plays a major role in immune evasion and is a barrier to the development of both natural and vaccine-induced protective immunity, it has been under-prioritized in the evaluation of malaria vaccine candidates. This study uses genomic approaches to evaluate genetic diversity in next generation malaria vaccine candidate PfRh5. We used targeted deep amplicon sequencing to identify non-synonymous Single Nucleotide Polymorphisms (SNPs) in PfRh5 (Reticulocyte-Binding Protein Homologue 5) in 189 P. falciparum positive samples from Southern Senegal and identified 74 novel SNPs. We evaluated the population prevalence of these SNPs as well as the frequency in individual samples and found that only a single SNP, C203Y, was present at every site. Many SNPs were unique to the individual sampled, with over 90% of SNPs being found in just one infected individual. In addition to population prevalence, we assessed individual level SNP frequencies which revealed that some SNPs were dominant (frequency of greater than 25% in a polygenomic sample) whereas most were rare, present at 2% or less of total reads mapped to the reference at the given position. Structural modeling uncovered 3 novel SNPs occurring under epitopes bound by inhibitory monoclonal antibodies, potentially impacting immune evasion, while other SNPs were predicted to impact PfRh5 structure or interactions with the receptor or binding partners. Our data demonstrate that PfRh5 exhibits greater genetic diversity than previously described, with the caveat that most of the uncovered SNPs are at a low overall frequency in the individual and prevalence in the population. The structural studies reveal that novel SNPs could have functional implications on PfRh5 receptor binding, complex formation, or immune evasion, supporting continued efforts to validate PfRh5 as an effective malaria vaccine target and development of a PfRh5 vaccine.