Dichotomous regulation of striatal plasticity by dynorphin.

Modulation of corticostriatal plasticity alters the information flow throughout basal ganglia circuits and represents a fundamental mechanism for motor learning, action selection, and reward. Synaptic plasticity in the striatal direct- and indirect-pathway spiny projection neurons (dSPNs and iSPNs) is regulated by two distinct networks of GPCR signaling cascades. While it is well-known that dopamine D2 and adenosine A2a receptors bi-directionally regulate iSPN plasticity, it remains unclear how D1 signaling modulation of synaptic plasticity is counteracted by dSPN-specific Gi signaling. Here, we show that striatal dynorphin selectively suppresses long-term potentiation (LTP) through Kappa Opioid Receptor (KOR) signaling in dSPNs. Both KOR antagonism and conditional deletion of dynorphin in dSPNs enhance LTP counterbalancing with different levels of D1 receptor activation. Behaviorally, mice lacking dynorphin in D1 neurons show comparable motor behavior and reward-based learning, but enhanced flexibility during reversal learning. These findings support a model in which D1R and KOR signaling bi-directionally modulate synaptic plasticity and behavior in the direct pathway.

Factors associated with suboptimal retention in HIV pre-exposure prophylaxis care among men who have sex with men.

Despite the efficacy of HIV pre-exposure prophylaxis (PrEP), retention in care in the United States remains suboptimal. The goal of this study was to explore factors that lead to suboptimal retention in PrEP care for men who have sex with men (MSM) in real-world clinical settings in the United States. Trained interviewers conducted semi-structured interviews with MSM (N = 49) from three clinics who had been engaged in PrEP care in the Midwest (n = 15), South (n = 15), and Northeast (n = 19) geographic regions and had experienced a lapse in PrEP use. Factors that emerged as related to suboptimal retention in PrEP care included structural factors such as transportation and out-of-pocket costs; social factors such as misinformation on media and in personal networks; clinical factors such as frequency and timing of appointments; and behavioral factors such as changes in sexual behavior and low perceived risk for HIV. Participants suggested reducing the out-of-pocket costs of medications and lab visits, having flexible appointment times, culturally responsive services, and comprehensive patient navigation to help retention in care. These findings leveraged real-world experiences and opinions of patients to inform gaps in current services and how to make changes to optimize PrEP care.

Preferences for HIV Preexposure Prophylaxis Products Among Black Women in the U.S.

In a nationwide sample of Black women in the U.S., we assessed preferences for HIV preexposure prophylaxis (PrEP) products, including long-acting injectable (LAI) PrEP and once-daily oral PrEP. Among 315 respondents, 32.1% were aware of PrEP and 40.6% were interested in using it; interest increased to 62.2% if PrEP were provided for free. Oral PrEP was the preferred option (51.1%), followed by LAI PrEP (25.7%), vaginal gel (16.5%), and vaginal ring (6.7%). When examining oral and LAI PrEP alone, most (62.7%) preferred oral PrEP. LAI PrEP was more likely to be preferred among respondents with concerns about healthcare costs or PrEP-related stigma, and among those who reported inconsistent condom use and multiple sexual partners. Although most Black women preferred oral PrEP, LAI PrEP may be appealing to a subset with social and structural barriers to PrEP use, such as cost and stigma, and those at increased risk of HIV infection.

Validation of the HIV Pre-exposure Prophylaxis Stigma Scale: Performance of Likert and Semantic Differential Scale Versions.

Stigma regarding HIV pre-exposure prophylaxis (PrEP) is commonly implicated as a factor limiting the scale-up of this highly effective HIV prevention modality. To quantify and characterize PrEP stigma, we developed and validated a brief HIV PrEP Stigma Scale (HPSS) among a group of 279 men who have sex with men (MSM). Scale development was informed by a theoretical model to enhance content validity. We assessed two scale versions, Semantic Differential and Likert, randomizing the order in which scales were presented to participants. Both scales demonstrated high internal consistency. The Likert scale had substantially better construct validity and was selected as the preferred option. Scale scores demonstrated construct validity through association with constructs of interest: healthcare distrust, HIV knowledge, perceived proportion of friends/partners on PrEP, perceived community evaluation of PrEP, and perceived effectiveness of PrEP. The scale accounted for 25% of the total variance in reported willingness to be on PrEP, indicating the substantial role PrEP stigma may have on decisions to initiate PrEP. Given increased efforts to roll-out PrEP, having a valid tool to determine the level and types of PrEP stigma in individuals, groups, and communities can help direct implementation plans, identify goals for stigma reduction, and monitor progress over time.

Developing and Assessing the Feasibility of a Home-based Preexposure Prophylaxis Monitoring and Support Program.

We piloted PrEP@Home, a preexposure prophylaxis system of remote laboratory and behavioral monitoring designed to replace routine quarterly follow-up visits with home care to reduce the patient and provider burden. The system was highly acceptable and in-demand for future use, and more than one-third of participants reported greater likelihood of persisting in care if available.

Neonatal mortality risk assessment using SNAPPE- II score in a neonatal intensive care unit.

BACKGROUND: There are many scoring systems to predict neonatal mortality and morbidity in neonatal intensive care units (NICU). One of the scoring systems is SNAPPE-II (Score for Neonatal Acute Physiology with Perinatal extension-II). This study was carried out to assess the validity of SNAPPE-II score (Score for Neonatal Acute Physiology with Perinatal Extension-II) as a predictor of neonatal mortality and duration of stay in a neonatal intensive care unit (NICU). METHODS: This prospective, observational study was carried out over a period of 12 months from June 2015 to May 2016. Two hundred fifty five neonates, who met the inclusion criteria admitted to NICU in tertiary care hospital, BPKIHS Hospital, Nepal were enrolled in the study and SNAPPE-II score was calculated. Receiver Operating Characteristic (ROC) curve was constructed to derive the best SNAPPE-II cut-off score for mortality. RESULTS: A total of 305 neonates were admitted to NICU over a period of one year. Among them, 255 neonates fulfilled the inclusion criteria. Out of 255 neonates, 45 neonates (17.6%) died and 210 were discharged. SNAPPE-II score was significantly higher among neonates who died compared to those who survived [median (IQR) 57 (42-64) vs. 22 (14-32), P < 0.001]. SNAPPE II score had discrimination to predict mortality with area under ROC Curve (AUC): 0.917 (95% CI, 0.854-0.980). The best cut - off score for predicting mortality was 38 with sensitivity 84.4%, specificity 91%, positive predictive value 66.7% and negative predictive value 96.5%. SNAPPE II score could not predict the duration of NICU stay (P = 0.477). CONCLUSION: SNAPPE- II is a useful tool to predict neonatal mortality in NICU. The score of 38 may be associated with higher mortality.

Behavioral Changes Following Uptake of HIV Pre-exposure Prophylaxis Among Men Who Have Sex with Men in a Clinical Setting.

We describe changes in sexual behaviors among men who have sex with men (MSM) following initiation of pre-exposure prophylaxis (PrEP) in a clinic-based sample of MSM initiating PrEP in Providence, Rhode Island. Data were collected at baseline, 3, and 6 months following PrEP initiation including total number of anal sex partners and condom use. A longitudinal mixed effects model assessed changes in number of partners and condom use over time, adjusting for age, race, and education. There was no statistically significant difference in total number of partners over time. There was a significant increase in number of condomless anal sex partners at the 6-month visit compared to baseline (mean change +1.31 partners, 95% confidence interval 0.09-2.53, P = 0.035). As condomless anal sex may increase following PrEP uptake, adherence counseling and efforts to retain patients in PrEP care, especially during periods of non-condom use, are important as PrEP is more widely implemented.

Motor learning in animal models of Parkinson's disease: Aberrant synaptic plasticity in the motor cortex.

In Parkinson's disease (PD), dopamine depletion causes major changes in the brain, resulting in the typical cardinal motor features of the disease. PD neuropathology has been restricted to postmortem examinations, which are limited to only a single time of PD progression. Models of PD in which dopamine tone in the brain is chemically or physically disrupted are valuable tools in understanding the mechanisms of the disease. The basal ganglia have been well studied in the context of PD, and circuit changes in response to dopamine loss have been linked to the motor dysfunctions in PD. However, the etiology of the cognitive dysfunctions that are comorbid in PD patients has remained unclear until now. In this article, we review recent studies exploring how dopamine depletion affects the motor cortex at the synaptic level. In particular, we highlight our recent findings on abnormal spine dynamics in the motor cortex of PD mouse models through in vivo time-lapse imaging and motor skill behavior assays. In combination with previous studies, a role of the motor cortex in skill learning and the impairment of this ability with the loss of dopamine are becoming more apparent. Taken together, we conclude with a discussion on the potential role for the motor cortex in PD, with the possibility of targeting the motor cortex for future PD therapeutics. © 2017 International Parkinson and Movement Disorder Society.

EphA7 signaling guides cortical dendritic development and spine maturation.

The process by which excitatory neurons are generated and mature during the development of the cerebral cortex occurs in a stereotyped manner; coordinated neuronal birth, migration, and differentiation during embryonic and early postnatal life are prerequisites for selective synaptic connections that mediate meaningful neurotransmission in maturity. Normal cortical function depends upon the proper elaboration of neurons, including the initial extension of cellular processes that lead to the formation of axons and dendrites and the subsequent maturation of synapses. Here, we examine the role of cell-based signaling via the receptor tyrosine kinase EphA7 in guiding the extension and maturation of cortical dendrites. EphA7, localized to dendritic shafts and spines of pyramidal cells, is uniquely expressed during cortical neuronal development. On patterned substrates, EphA7 signaling restricts dendritic extent, with Src and Tsc1 serving as downstream mediators. Perturbation of EphA7 signaling in vitro and in vivo alters dendritic elaboration: Dendrites are longer and more complex when EphA7 is absent and are shorter and simpler when EphA7 is ectopically expressed. Later in neuronal maturation, EphA7 influences protrusions from dendritic shafts and the assembling of synaptic components. Indeed, synaptic function relies on EphA7; the electrophysiological maturation of pyramidal neurons is delayed in cultures lacking EphA7, indicating that EphA7 enhances synaptic function. These results provide evidence of roles for Eph signaling, first in limiting the elaboration of cortical neuronal dendrites and then in coordinating the maturation and function of synapses.

A Multicomponent Library Resource Model to Enhance Academic Global Health Education Among Residency Programs.

Global health is becoming an increasingly important component of medical education. Medical libraries have an opportunity to assist global health residents with their information needs, but first it is important to identify what those needs are and how best they can be addressed. This article reports a collaboration between global health faculty and an academic medical librarian to assess the information needs of global health pathway residents and how assessment data are used to create a multicomponent program designed to enhance global health education.

EGFR Targeted Theranostic Nanoemulsion for Image-Guided Ovarian Cancer Therapy.

PURPOSE: Platinum-based therapies are the first line treatments for most types of cancer including ovarian cancer. However, their use is associated with dose-limiting toxicities and resistance. We report initial translational studies of a theranostic nanoemulsion loaded with a cisplatin derivative, myrisplatin and pro-apoptotic agent, C6-ceramide. METHODS: The surface of the nanoemulsion is annotated with an endothelial growth factor receptor (EGFR) binding peptide to improve targeting ability and gadolinium to provide diagnostic capability for image-guided therapy of EGFR overexpressing ovarian cancers. A high shear microfludization process was employed to produce the formulation with particle size below 150 nm. RESULTS: Pharmacokinetic study showed a prolonged blood platinum and gadolinium levels with nanoemulsions in nu/nu mice. The theranostic nanoemulsions also exhibited less toxicity and enhanced the survival time of mice as compared to an equivalent cisplatin treatment. CONCLUSIONS: Magnetic resonance imaging (MRI) studies indicate the theranostic nanoemulsions were effective contrast agents and could be used to track accumulation in a tumor. The MRI study additionally indicate that significantly more EGFR-targeted theranostic nanoemulsion accumulated in a tumor than non-targeted nanoemulsuion providing the feasibility of using a targeted theranostic agent in conjunction with MRI to image disease loci and quantify the disease progression.

Dopamine D2 receptors regulate collateral inhibition between striatal medium spiny neurons.

The principle neurons of the striatum are GABAergic medium spiny neurons (MSNs), whose collateral synapses onto neighboring neurons play critical roles in striatal function. MSNs can be divided by dopamine receptor expression into D1-class and D2-class MSNs, and alterations in D2 MSNs are associated with various pathological states. Despite overwhelming evidence for D2 receptors (D2Rs) in maintaining proper striatal function, it remains unclear how MSN collaterals are specifically altered by D2R activation. Here, we report that chronic D2R stimulation regulates MSN collaterals in vitro by presynaptic and postsynaptic mechanisms. We used corticostriatal cultures from mice in which MSN subtypes were distinguished by fluorophore expression. Quinpirole, an agonist for D2/3 receptors, was used to chronically activate D2Rs. Quinpirole increased the rate and strength of collateral formation onto D2R-containing MSNs as measured by dual whole-cell patch-clamp recordings. Additionally, these neurons were more sensitive to low concentrations of GABA and exhibited an increase in gephyrin puncta density, suggesting increased postsynaptic GABAA receptors. Last, quinpirole treatment increased presynaptic GABA release sites, as shown by increased frequency of sIPSCs and mIPSCs, correlating with increased VGAT (vesicular GABA transporter) puncta. Combined with the observation that there were no detectable differences in sensitivity to specific GABAA receptor modulators, we provide evidence that D2R activation powerfully transforms MSN collaterals via coordinated presynaptic and postsynaptic alterations. As the D2 class of MSNs is highly implicated in Parkinson's disease and other neurological disorders, our findings may contribute to understanding and treating the changes that occur in these pathological states.

Distinct roles for somatically and dendritically synthesized brain-derived neurotrophic factor in morphogenesis of dendritic spines.

Dendritic spines undergo the processes of formation, maturation, and pruning during development. Molecular mechanisms controlling spine maturation and pruning remain largely unknown. The gene for brain-derived neurotrophic factor (BDNF) produces two pools of mRNA, with either a short or long 3' untranslated region (3' UTR). Our previous results show that short 3' UTR Bdnf mRNA is restricted to cell bodies, whereas long 3' UTR Bdnf mRNA is also trafficked to dendrites for local translation. Mutant mice lacking long 3' UTR Bdnf mRNA display normal spines at 3 weeks of age, but thinner and denser spines in adults compared to wild-type littermates. These observations suggest that BDNF translated from long 3' UTR Bdnf mRNA, likely in dendrites, is required for spine maturation and pruning. In this study, using rat hippocampal neuronal cultures, we found that knocking down long 3' UTR Bdnf mRNA blocked spine head enlargement and spine elimination, whereas overexpressing long 3' UTR Bdnf mRNA had the opposite effect. The effect of long 3' UTR Bdnf mRNA on spine head enlargement and spine elimination was diminished by a human single-nucleotide polymorphism (SNP, rs712442) in its 3' UTR that inhibited dendritic localization of Bdnf mRNA. Furthermore, we found that overexpression of either Bdnf mRNA increased spine density at earlier time points. Spine morphological alterations were associated with corresponding changes in density, size, and function of synapses. These results indicate that somatically synthesized BDNF promotes spine formation, whereas dendritically synthesized BDNF is a key regulator of spine head growth and spine pruning.

Targeted transferrin-modified polymeric micelles: enhanced efficacy in vitro and in vivo in ovarian carcinoma.

In this study, transferrin (Tf)-modified poly(ethylene glycol)-phosphatidylethanolamine (mPEG-PE) micelles loaded with the poorly water-soluble drug, R547 (a potent and selective ATP-competitive cyclin-dependent kinase (CDK) inhibitor), were prepared and evaluated for their targeting efficiency and cytotoxicity in vitro and in vivo to A2780 ovarian carcinoma cells, which overexpress transferrin receptors (TfR). At 10 mM lipid concentration, both Tf-modified and plain micelles solubilized 800 µg of R547. Tf-modified micelles showed enhanced interaction with A2780 ovarian carcinoma cells in vitro. The involvement of TfR in endocytosis of Tf-modified micelles was confirmed by colocalization studies of micelle-treated cells with the endosomal marker Tf-Alexa488. We confirmed endocytosis of micelles in an intact form with micelles loaded with a fluorescent dye and additionally labeled with fluorescent lipid. The in vitro cytotoxicity and in vivo tumor growth inhibition studies in A2780-tumor bearing mice confirmed the enhanced efficacy of Tf-modified R547-loaded micelles compared to free drug solution and to nonmodified micelles. The results of this study demonstrate the potential application of Tf-conjugated polymeric micelles in the treatment of tumors overexpressing TfR.

Radiofrequency ablation-induced upregulation of hypoxia-inducible factor-1α can be suppressed with adjuvant bortezomib or liposomal chemotherapy.

PURPOSE: To characterize upregulation of hypoxia-inducible factor (HIF)-1α after radiofrequency (RF) ablation and the influence of an adjuvant HIF-1α inhibitor (bortezomib) and nanodrugs on modulating RF ablation-upregulated hypoxic pathways. MATERIALS AND METHODS: Fisher 344 rats (n = 68) were used. First, RF ablation-induced periablational HIF-1α expression was evaluated in normal liver or subcutaneous R3230 tumors (14-16 mm). Next, the effect of varying RF ablation thermal dose (varying tip temperature 50°C-90°C for 2-20 minutes) on HIF-1α expression was studied in R3230 tumors. Third, RF ablation was performed in R3230 tumors without or with an adjuvant HIF-1α inhibitor, bortezomib (single intraperitoneal dose 0.1 mg/kg). Finally, the combination RF ablation and intravenous liposomal chemotherapeutics with known increases in periablational cellular cytotoxicity (doxorubicin, paclitaxel, and quercetin) was assessed for effect on periablational HIF-1α. Outcome measures included immunohistochemistry of HIF-1α and heat shock protein 70 (marker of nonlethal thermal injury). RESULTS: RF ablation increased periablational HIF-1α in both normal liver and R3230 tumor, peaking at 24-72 hours. Tumor RF ablation had similar HIF-1α rim thickness but significantly greater percent cell positivity compared with hepatic RF ablation (P < .001). HIF-1α after ablation was the same regardless of thermal dose. Bortezomib suppressed HIF-1α (rim thickness, 68.7 µm ± 21.5 vs 210.3 µm ± 85.1 for RF ablation alone; P < .02) and increased ablation size (11.0 mm ± 1.5 vs 7.7 mm ± 0.6 for RF ablation alone; P < .002). Finally, all three nanodrugs suppressed RF ablation-induced HIF-1α (ie, rim thickness and cell positivity; P < .02 for all comparisons), with liposomal doxorubicin suppressing HIF-1α the most (P < .03). CONCLUSIONS: RF ablation upregulates HIF-1α in normal liver and tumor in a temperature-independent manner. This progrowth, hypoxia pathway can be successfully suppressed with an adjuvant HIF-1α-specific inhibitor, bortezomib, or non-HIF-1α-specific liposomal chemotherapy.

Phospholipid-modified polyethylenimine-based nanopreparations for siRNA-mediated gene silencing: implications for transfection and the role of lipid components.

The clinical application of gene silencing mediated by small interfering RNA (siRNA) has been limited by the lack of efficient and safe carriers. Phospholipid modification of low molecular weight polyethylenimine (PEI 1.8 kDa) dramatically increased its gene down-regulation capacity while keeping cytotoxicity levels low. The silencing efficacy was highly dependent on the nature of the lipid grafted to PEI and the polymer/siRNA ratio employed. Phosphoethanolamine (DOPE and DPPE) and phosphocholine (PC) conjugation did not change the physicochemical properties and siRNA binding capacity of PEI complexes but had a large impact on their transfection and ability to down-regulate Green Fluorescent Protein (GFP) expression (60%, 30% and 5% decrease of GFP expression respectively). We found that the micelle-forming structure of DOPE and DPPE-PEI dramatically changed PEI's interaction with cell membranes and played a key role in promoting PEI 1.8 kDa transfection, completely ineffective in the absence of the lipid modification. FROM THE CLINICAL EDITOR: While siRNA-based gene silencing methods could have numerous clinical applications, efficient delivery remains a major challenge. This team reports that DOPE-PEI and DPPE-PEI based micelle-forming nanostructures may be able to provide an efficient vector for siRNA transfection.

Assessment of control of bronchial asthma in children using Childhood Asthma Control Test.

BACKGROUND: The use of Childhood Asthma Control Test (C-ACT) has been advised for monitoring asthma control by the Global Initiative for Asthma (GINA) guidelines. OBJECTIVE: To validate the tool C-ACT for the assessment of control of asthma and to examine the correlation between C-ACT score and lung function assessed by forced expiratory volume in one second (FEV1). METHODS: This was a prospective observational study conducted between January 2010 to January 2011. Children diagnosed to have bronchial asthma and aged 5 to 14 years, were enrolled in the study. Asthma severity and control status were classified according to the National Asthma Education and Prevention Programme (NAEPP) and GINA guidelines, respectively. Patients were followed-up at three and six months and C-ACT and spirometric measurements were obtained. RESULTS: Significant positive correlations were found between C-ACT score and FEV1 at enrollment (r = 0.772) (p < 0.001), three months (r = 0.815) (p < 0.001) and at six months follow-up (r = 0.908) (p < 0.001). Baseline C-ACT score was useful for predicting the levels of control of asthma upto three months (0.004), but not at six months follow-up (0.787). A cut-off C-ACT value of > or = 19 had a sensitivity, specificity, positive predictive value, negative predictive value and area under the curve (AUC) 98.5%, 89.1%, 94.9%, 96.6%, 0.717, respectively for the control of asthma. CONCLUSION: C-ACT is a simple and feasible tool to assess and predict the levels of control in children with bronchial asthma upto three months.

High Rates of Missed HIV Testing Among Oral PrEP Users in the United States From 2018-2021: A National Assessment on Compliance With HIV Testing Recommendations of the CDC PrEP Guidelines.

Background: The US Centers for Disease Control and Prevention recommends HIV testing every 3 months in oral PrEP users. We performed a national assessment of HIV testing compliance among oral PrEP users. Methods: We analyzed 408 910 PrEP prescriptions issued to 39 809 PrEP users using a national insurance claims database that contained commercial and Medicaid claims. We identified PrEP use based on pharmacy claims and outpatient diagnostic coding. We evaluated the percentage of PrEP prescription refills without HIV testing (identified by CPT codes) within the prior 3, 6, and 12 months using time to event methods. We performed subgroup and multivariate analyses by age, gender, race, insurance type, and geography. Results: Of 39 809 persons, 36 197 were commercially insured, 3612 were Medicaid-insured, and 96% identified as male; the median age (interquartile range) was 34 (29-44) years, and the Medicaid-insured PrEP users were 24% Black/African American, 44% White, and 9% Hispanic/Latinx. Within the prior 3, 6, and 12 months, respectively, the percentage of PrEP prescription fills in individuals without HIV Ag/Ab testing was 34.3% (95% CI, 34.2%-34.5%), 23.8% (95% CI, 23.7%-23.9%), and 16.6% (95% CI, 16.4%-16.7%), and the percentage without any type of HIV test was 25.8% (95% CI, 25.6%-25.9%), 14.6% (95% CI, 14.5%-14.7%), and 7.8% (95% CI, 7.7%-7.9%). Conclusions: Approximately 1 in 3 oral PrEP prescriptions were filled in persons who had not received an HIV Ag/Ab test within the prior 3 months, with evidence of health disparities. These findings inform clinical PrEP monitoring efforts and compliance with national HIV testing guidance to monitor PrEP users.

First Case of HIV Seroconversion With Integrase Resistance Mutations on Long-Acting Cabotegravir for Prevention in Routine Care.

Background: Long-acting cabotegravir (CAB-LA) is highly effective for HIV prevention, but delayed HIV diagnoses and integrase strand transfer inhibitor (INSTI) resistance were observed in trials. We report the first case in routine clinical care of HIV infection on CAB-LA with INSTI resistance. Methods: The SeroPrEP study enrolls individuals in the United States who acquire HIV on pre-exposure prophylaxis modalities to assess diagnostics, antiretroviral (ARV) drug levels, resistance, and treatment outcomes. Resistance mutations in full-length HIV-1 integrase were identified by single-genome sequencing (SGS). Cabotegravir concentrations in plasma and hair segments were measured by liquid chromatography-tandem mass spectrometry. Results: A 23-year-old gender-nonbinary person, male at birth, restarted CAB-LA 6 months after discontinuation due to losing insurance. Prior to restart, HIV-1 RNA was not detected, but 20 days elapsed before CAB-LA injection. After the second CAB-LA injection, HIV antigen/antibody returned reactive (HIV-1 RNA 451 copies/mL). SGS of plasma HIV-1 RNA identified INSTI mutation Q148R in 2/24 sequences 2 days postdiagnosis; commercial genotype failed amplification. Cabotegravir hair concentration was 0.190 ng/mg 2 weeks prediagnosis; plasma cabotegravir was high (3.37 µg/mL; ∼20× PA-IC90) 14 days postdiagnosis. Viral suppression was maintained for 6 months on darunavir/cobicistat/emtricitabine/tenofovir alafenamide, then switched to doravirine + emtricitabine/tenofovir alafenamide due to nausea. Conclusions: In this first case of HIV infection on CAB-LA with INSTI resistance in routine care, cabotegravir resistance was detected only with a sensitive research assay. Accelerated pathways to minimize time between HIV testing and CAB-LA initiation are needed to optimize acute HIV detection and mitigate resistance risk. Sustained product access regardless of insurance is imperative to reduce HIV infections on CAB-LA.