Women with HIV (WWH) face increased risk for cervical cancer (CC) and sexual trauma. This cross-sectional analysis of the Florida Cohort Study (2019-2022) examined associations between any three lifetime sexual traumas (harassment, unwanted touch, or forced sex), demographics, and CC screening among 117 WWH aged 18+ without a hysterectomy. Participants self-reported lifetime experiences of three sexual traumas and CC screening within the past three years. Among 117 WWH, 19% reported no CC screening within the past three years, while 47% reported any lifetime sexual trauma. Any lifetime sexual trauma was not associated with CC screening. No CC screening within the past three years was reported more frequently among WWH who experienced any lifetime sexual trauma compared to those without (22% vs. 16%, p = 0.46); younger women (<30 years: 50% vs. 30-65 years: 15%, >65 years: 43%, p = 0.03); non-Black women (25% vs. Black: 13%, p = 0.09), and those with less than some college education (25% vs. some college or more: 10%, p = 0.05). Although sexual trauma associations were not statistically significant, trends suggest sexual trauma may influence CC screening behaviors. Demographic differences underscore the need for targeted interventions. Further research could explore strategies, like home-based HPV self-sampling, to enhance CC screening among WWH.Abbreviations: CC: cervical cancer; IRB: institutional review board; NIAAA: National Institute on Alcohol Abuse and Alcoholism; Pap: Papanicolaou; PWH: people with HIV; WWH: women with HIV; WWOH: women without HIV.

Acute pancreatitis (AP) is a potentially fatal disease of the exocrine pancreas. The disease pathogenesis remains obscure, and no effective treatment is available. Uncontrolled, deregulated inflammation is a major cause of systemic complications in AP; however, approaches to reduce inflammation in human disease by inhibiting inflammatory mediators encountered multiple challenges and have not been successful. Oxidative stress drives inflammation in many diseases but its role in AP remains poorly understood. This study evaluates the role of NRF2, the master antioxidant defense transcription factor, in the inflammatory response and severity of experimental AP in mouse and cellular (ex vivo) models. Pancreas-specific genetic ablation of NRF2 worsened nonalcoholic and alcohol-mediated AP by downregulating antioxidant gene expression and upregulating inflammatory mediators, as shown by RNA-seq analysis. Pancreatic NRF2 was activated in the experimental AP models; however, this activation was insufficient to prevent oxidative stress and inflammation. Additional pharmacologic NRF2 activation with sulforaphane markedly reduced oxidative stress, inflammation, and other pancreatitis responses; importantly, it ameliorated a recurrent episode of AP. The results highlight a major role of NRF2 in protecting against oxidative stress and inflammation in AP; and suggest pharmacologic activation of NRF2 as a promising therapeutic strategy to mitigate inflammation and reduce the severity of pancreatitis.

Clinical syndromes or diseases with complex etiology often require multiple treatments, each addressing one specific aspect of the disease. Such treatments are typically administered sequentially in an integrated fashion. For example, in alcohol-associated hepatitis (AH), an acute liver disease caused by excessive alcohol drinking, successful treatment requires therapies that reduce liver inflammation during the acute phase, followed by interventions that address the underlying alcohol use disorder (AUD) to achieve optimal outcomes. Selecting an optimal treatment combination, however, presents great challenges in study design due to the involvement of multiple drug combinations and treatment phases. In this paper, we describe a new trial design based on a Bayesian model that connects the outcomes from the acute and subsequent treatment phases. We refer to this design as the Bayesian Optimal Adaptive Design for Sequentially Integrated Therapies (BIT) design. BIT incorporates multiple interim analyses with adaptive stopping rules for both futility and superiority, enhancing efficiency while controlling the family-wise type I error rate and maximizing statistical power. We illustrate the use of BIT design in a clinical trial comparing the efficacy of integrated therapy for severe AH, with sample size determination and design parameter optimization. Simulation studies show that the design possesses excellent operating characteristics, including experiment-wise type I error rate control. Although the design's development is motivated by studies of AH treatment, the design framework is broadly applicable to other complex diseases requiring sequentially delivered therapies. R codes are provided for BIT implementation.

In some children with autism, fever improves cognition. However, it remains unclear whether the thermal or immune components of fever are responsible for this improvement. Using the Scn2a+/- autism mouse model, we demonstrate that fever-like temperatures, independent of direct immune activation, normalize cognitive function. In behavioral tests assessing learning of an escape route, Scn2a+/- juvenile mice at normal body temperature fail to learn, whereas wild-type mice at normal body temperature and Scn2a+/- mice exposed to infrared light-induced fever, either alone or in combination with immune activation by LPS, exhibit normal learning. Notably, mice with fever alone demonstrated the fastest escape times. Additionally, in novelty recognition tests of textured objects, Scn2a+/- mice exhibited an increased preference for familiar objects, but fever-like temperatures induced by infrared light exposure or hypothalamic stimulation reversed this abnormality. In the somatosensory cortex, where object texture is perceived, fever-like temperatures reduced excess spiking in Scn2a+/- pyramidal neurons by increasing potassium channel activation and spike threshold. Chemogenetically reducing spiking at normal temperatures replicated the effects of fever. These findings suggest that thermal fever may offer general cognitive benefits in autism.

The spinal cord critically regulates startle responses through local excitatory and inhibitory circuits. The glycine receptor alpha 1 subunit (GlyRα1) mediates the primary inhibitory neurotransmission in the spinal cord, however, the contribution of spinal glycinergic inhibition to startle regulation remains poorly understood. Here, we show that GlyRα1 controls startle behavior in a cell-type- and region-specific manner. GlyRα1 deletion in ChAT-positive spinal neurons markedly enhances startle responses and c-Fos activation in spinal motor neurons as well as excitatory interneurons. In contrast, GlyRα1 deletion in inhibitory interneurons suppresses startle behavior while selectively increasing spinal c-Fos activation in inhibitory but not excitatory interneurons. Consistent with these findings, intraspinal AAV-Cre induced deletion of GlyRα1 without cell-type specificity increases startle responses, whereas deletion from spinal CamK2α-positive cells, which predominantly overlap with glycinergic inhibitory interneurons, attenuates startle reflexes. By contrast, deletion of GlyRα1 from brainstem RtTg CamK2α-positive cells, which are predominantly glutamatergic, enhances startle responses. GlyRα1 deficiency in glycinergic neurons reduces the amplitude of puff-applied glycine-elicited currents without affecting synaptic inhibitory and excitatory neurotransmission in the spinal cord. Together, these findings identify spinal GlyRα1 subunits as a cell-type specific regulator of startle behavior and reveal opposing contributions of GlyRα1 signaling in spinal inhibitory interneurons and motor/excitatory output pathways.

Alcohol withdrawal is a common and potentially life-threatening condition that is often a barrier to voluntary discontinuation of heavy alcohol use. Given the wide range of alcohol withdrawal severity and difficulty predicting an individual's alcohol withdrawal course, managing alcohol withdrawal in an ambulatory setting can be difficult. This article explores the pathophysiology of alcohol withdrawal and risk factors for severe alcohol withdrawal, as well as provides a framework for ambulatory medically managed withdrawal in the clinic setting.