Motivated Knowledge Acquisition: Implicit Self-Theories and the Preference for Knowledge Breadth or Depth.

Implicit self-theories posit that individuals ascribe to one of two beliefs regarding the self: an incremental theory motivated by learning goals and an entity theory motivated by performance goals. This work proposes that these theories-and their underlying motivations-reflect individuals' preferences for different knowledge types. Specifically, we propose that incremental theorists prefer knowledge that expands their understanding of diverse experiences within a category (i.e., knowledge breadth), whereas entity theorists prefer knowledge that refines their understanding of a preferred experience within a category (i.e., knowledge depth). Five studies show the effect of implicit self-theories on individuals' preferences for knowledge breadth and depth and the role of learning and performance goals in motivating these knowledge preferences. We address alternative explanations related to general openness, risk-seeking, and perceived quality differences, and we demonstrate the role of negative feedback in reversing these knowledge preferences.

HIV Pre-Exposure Prophylaxis: New and Upcoming Drugs to Address the HIV Epidemic.

Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) provides a critical intervention toward ending the HIV epidemic and protecting people with reasons to utilize PrEP. PrEP options continue to expand as new administration modalities offer the potential to tailor PrEP use for individual success. We have provided the evidence for new and emerging antiretroviral agents for PrEP (cabotegravir, lenacapavir, dapivirine, and broadly neutralizing antibodies), divided into pharmacology, animal model, and human data, accompanied by a summary and suggested place in therapy. Cabotegravir is a US Food and Drug Administration (FDA)-approved intramuscular injection given every 2 months with a strong body of evidence demonstrating efficacy for HIV PrEP, lenacapavir administered subcutaneously every 6 months is currently under investigation for HIV PrEP, dapivirine vaginal ring is an available PrEP option for women in certain areas of Africa, and broadly neutralizing monoclonal antibodies have been challenged in demonstrating efficacy in phase 1-2 study for HIV PrEP to date. Clinical literature for individual agents is discussed with data from major studies summarized in tables. This review provides a detailed overview of recently available and premier candidate PrEP drugs.

Remdesivir-induced conduction abnormalities: A molecular model-based explanation.

Purpose: Remdesivir use in COVID-19 is associated with cardiac conduction abnormalities from unclear mechanisms. A proposed mechanism is the bioaccumulation of the intermediate metabolite GS-441524 resulting in exogenous activation of cardiac adenosine A1 due to the structural similarity between adenosine and GS-441524. The prolonged half-life of GS-441524 can result in sustained activation of adenosine A1 receptors. In this study, we used molecular modeling of adenosine, GS-441524 and the adenosine A1 receptor to assess the potential mechanistic association of the proposed mechanism. Methods: Adenosine and GS-441524 structures were acquired from the PubChem database. Ligand docking was carried out using UCSF Chimera. Models were chosen based on greatest binding affinity and minimum root mean square deviation. Figures of resulting structural models were prepared using UCSF Chimera or PyMOL 2.3.5. Results: By modeling the interaction between the A1 G protein complex and both adenosine and GS-441524, we found that the proposed mechanism of exogenous A1 receptor activation is feasible based on docking compatibility. Conclusion: The proposed mechanism of exogenous cardiac A1 receptor activation from bioaccumulation of GS-441524 as a cause of observed cardiac conduction abnormalities with the use of remdesivir in COVID-19 is viable. Further studies are needed to assess causality.

Proton pump inhibitors: Understanding the associated risks and benefits of long-term use.

PURPOSE: Proton pump inhibitors (PPIs) are widely prescribed medications. Various adverse clinical effects of PPIs have been reported in the literature, particularly over the past decade. The purpose of this article is to review published data primarily describing adverse effects associated with PPI use and to help clinicians determine which patients may still benefit from therapy despite safety concerns. SUMMARY: Associations between PPIs and the following have been described: bone fracture, acute and chronic kidney disease, gastrointestinal infections, deficiencies in vitamin B12 and magnesium, and coronavirus disease 2019 and respiratory infections. For inclusion in this review, studies must have evaluated potential adverse events associated with PPIs as a primary or secondary objective. Increased risks of bone fracture, acute and chronic kidney disease, gastrointestinal infections, and magnesium deficiency were consistently reported, albeit mostly in studies involving low-quality data (case-control and/or observational studies) and subject to bias. In the only pertinent randomized controlled trial to date, chronic pantoprazole use was associated with a greater risk of enteric infections relative to placebo use; there was no significant between-group difference in any other adverse event evaluated. PPIs continue to be recommended by the American College of Gastroenterology as a first-line treatment for management of gastroesophageal reflux disease and in the acute period following upper gastrointestinal and ulcer bleeding. CONCLUSION: Higher-quality data is needed to better understand PPI-associated risks of the adverse effects listed above. Until then, clinicians may consider greater vigilance with PPI use; however, the data does not demonstrate a need for wide adoption of de-escalation strategies solely out of safety concerns.

Cabotegravir: a novel HIV integrase inhibitor combined with rilpivirine as the first long-acting injectable program for the treatment of HIV infection.

Cabotegravir, a novel HIV integrase inhibitor, shares structural similarity with dolutegravir and bictegravir. Its oral half-life is 32 hours, but cabotegravir nanosuspension for intramuscular injection yields half-lives ranging from 25 to 54 days, enabling extended interval dosing. Drug interactions are minimal, although oral doses require spacing from polyvalent cations, and potent uridine glucuronosyltransferase induction (e.g., rifampin, carbamazepine) requires avoidance due to anticipated subtherapeutic cabotegravir exposure through extended intervals. Randomized clinical trials combined cabotegravir treatment with rilpivirine to demonstrate treatment efficacy in patients living with HIV who had attained virologic suppression, lacked known/suspected mutations to either component, and had not experienced prior HIV treatment failure. Together, oral cabotegravir and rilpivirine maintained viral suppression in the LATTE study while the combination, given intramuscularly, performed comparably to conventional oral therapy in LATTE-2. FLAIR and ATLAS, respectively, demonstrated HIV suppression maintenance for monthly injections in treatment-naive participants and treatment-experienced patients, with ATLAS-2M supporting the efficacy of injections given every 2 months. Investigations to date show an excellent safety profile. Injectable cabotegravir causes short-lived, mild injection site reactions (primarily administration site pain/soreness) that decrease in frequency over time, produce attributable discontinuation rates of at least 2%, and generate satisfaction scores that favor injectable therapy over oral therapy. Virologic failure with resistance development is rare, primarily occurs in the first year of therapy, and is associated with baseline proviral DNA mutations to coadministered rilpivirine. A key component of the first U.S. Food and Drug Administration (FDA)-approved injectable maintenance treatment program for HIV, injectable cabotegravir heralds a new era in HIV treatment innovation. Here we provide a detailed review of the clinical pharmacology, administration and available formulations of the novel HIV integrase inhibitor cabotegravir with in-depth analysis of the clinical trial data, safety, satisfaction and viral resistance development when combined with rilpivirine as the first long-acting injectable program for the treatment of HIV infection.

Hepatotoxicity of contemporary antiretroviral drugs.

PURPOSE OF REVIEW: To date, more than 30 antiretroviral drugs have been approved by the Food and Drug Administration for the treatment of HIV infection. As new drugs with better efficacy and safety profile become available for clinical practice, older drugs are either withdrawn from the market or become no longer actively prescribed. We review hepatotoxicity associated with contemporary antiretroviral drugs, with emphasis on data from the past 3 years. RECENT FINDINGS: Although less robust data exists for side effects of contemporary antiretroviral medications recently approved for the management of HIV (i.e., doravirine, ibalizumab, fostemsavir, cabotegravir), the risks of substantial hepatotoxicity appears to be minimal with these agents. SUMMARY: Although newer antiretroviral drugs are better tolerated than their earlier counterparts, they are not completely devoid of adverse drug reactions, including hepatotoxicity. Monitoring patients on antiretroviral therapy for treatment-emergent liver injury should continue to be part of routine clinical care.

Lacunar cerebral infarction following endovascular interventions for phlegmasia cerulea dolens.

Phlegmasia cerulea dolens is a rare presentation of deep venous thrombus treated with catheter directed thrombolysis and pharmacomechanical thrombectomy. This is the case of a 78-year-old woman who underwent catheter directed thrombolysis to treat phlegmasia cerulea dolens and subsequently developed left-sided hemiplegia and expressive aphasia in the setting of an international normalized ratio of 2.0. Further imaging revealed a lacunar infarct in the right thalamus with a middle cerebral artery distribution. Further workup revealed a patent foramen ovale. We highlight the unexpected enigmatic consequence from multimodal endovascular intervention, the consequence of long-term inferior vena cava filters.

Hepatotoxicity of Contemporary Antiretroviral Drugs: A Review and Evaluation of Published Clinical Data.

Contemporary antiretroviral agents afford enhanced potency and safety for patients living with HIV. Newer antiretroviral drugs are often better tolerated than those initially approved in the early stages of the HIV epidemic. While the safety profile has improved, adverse drug reactions still occur. We have segregated the antiretroviral agents used in contemporary practice into class groupings based on their mechanism of antiviral activity (non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors, and entry inhibitors) while providing a review and discussion of the hepatoxicity seen in the most relevant clinical literature published to date. Clinical literature for individual agents is discussed and agent comparisons afforded within each group in tabular format. Our review will provide a summative overview of the incidence and medications associated with hepatic adverse reactions linked to the use of contemporary antiretroviral drugs.

A retrospective evaluation of highly active antiretroviral therapy simplification in patients with end-stage renal disease receiving hemodialysis.

Antiretroviral (ARV) therapy in people living with HIV (PLWH) and end-stage renal disease (ESRD) on hemodialysis (HD) is complicated, requiring renally adjusted nucleoside reverse transcriptase inhibitors (NRTIs) and daily administration of non-renally eliminated agents. Recent data in PLWH with ESRD on HD demonstrate maintenance of viral suppression (82% with viral loads (VLs) <50 copies/mL) and favorable safety/tolerability profiles after ARV simplification with a fixed dose combination single tablet [elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF)]. Extrapolation of these data to all F/TAF formulations would allow ARV simplification to most PLWH with ESRD receiving HD. The objective of this retrospective study was to identify if ARV-experienced PLWH with ESRD on HD receiving renally adjusted NRTIs may be simplified to once daily ARV formulations without adverse effects while maintaining viral suppression. This single-center retrospective analysis assessed virologic control (3-12 months) and ARV tolerability post-regimen simplification (primarily NRTI once-daily dose adjustment) in PLWH with ESRD on thrice weekly HD receiving human immunodeficiency virus (HIV) care in an ambulatory clinic. Seventeen PLWH with ESRD on HD were included after documented ARV simplification. At 12 months, 12 patients (71%) remained undetectable (HIV VL <50 copies/mL) with two additional maintaining viral suppression (<200 copies/mL). One patient remained undetectable at month eight but became non-adherent with viral rebound. Two patients did not complete the 6- and 12-month evaluation after documented nonadherence (N = 1) and an adverse effect (pruritus) (N = 1). At 12 months, virologic suppression and tolerability resulted after a simplified ARV regimen including once daily F/TAF was initiated in PLWH with ESRD on thrice weekly HD with a reduction in pill burden.

The Malleable Efficacy of Willpower Theories.

Emerging research documents the self-control consequences of individuals' theories regarding the limited nature of willpower, such that unlimited theorists consistently demonstrate greater self-control than limited theorists. The purpose of the present research was to build upon prior work on self-validation and perceptions of mental fatigue to demonstrate when self-control is actually impaired by endorsing an unlimited theory and-conversely-enhanced by endorsing a limited theory. Four experiments show that fluency reinforces the documented effects of individuals' willpower theories on self-control, while disfluency reverses the documented effects of individuals' willpower theories on self-control. Moreover, these effects are driven by differential perceptions of mental fatigue-perceptions altered by individuals' level of confidence in their willpower theory-and are bound by conditions that promote effortful thought. Collectively, these findings point to the malleable efficacy of willpower theories and the importance of belief confidence in dictating this malleability and in modulating subsequent self-control behavior.

Decision sidestepping: How the motivation for closure prompts individuals to bypass decision making.

We all too often have to make decisions-from the mundane (e.g., what to eat for breakfast) to the complex (e.g., what to buy a loved one)-and yet there exists a multitude of strategies that allows us to make a decision. This work focuses on a subset of decision strategies that allows individuals to make decisions by bypassing the decision-making process-a phenomenon we term decision sidestepping. Critical to the present manuscript, however, we contend that decision sidestepping stems from the motivation to achieve closure. We link this proposition back to the fundamental nature of closure and how those seeking closure are highly bothered by decision making. As such, we argue that the motivation to achieve closure prompts a reliance on sidestepping strategies (e.g., default bias, choice delegation, status quo bias, inaction inertia, option fixation) to reduce the bothersome nature of decision making. In support of this framework, five experiments demonstrate that (a) those seeking closure are more likely to engage in decision sidestepping, (b) the effect of closure on sidestepping stems from the bothersome nature of decision making, and (c) the reliance on sidestepping results in downstream consequences for subsequent choice. Taken together, these findings offer unique insight into the cognitive motivations stimulating a reliance on decision sidestepping and thus a novel framework by which to understand how individuals make decisions while bypassing the decision-making process. (PsycINFO Database Record

The self-control consequences of political ideology.

Evidence from three studies reveals a critical difference in self-control as a function of political ideology. Specifically, greater endorsement of political conservatism (versus liberalism) was associated with greater attention regulation and task persistence. Moreover, this relationship is shown to stem from varying beliefs in freewill; specifically, the association between political ideology and self-control is mediated by differences in the extent to which belief in freewill is endorsed, is independent of task performance or motivation, and is reversed when freewill is perceived to impede (rather than enhance) self-control. Collectively, these findings offer insight into the self-control consequences of political ideology by detailing conditions under which conservatives and liberals are better suited to engage in self-control and outlining the role of freewill beliefs in determining these conditions.