Levetiracetam prevents neurophysiological changes and preserves cognitive function in the HIV-1 TAT transgenic mouse model of HIV-associated neurocognitive disorder.

HIV-associated neurocognitive disorder (HAND) affects nearly half of the 39 million people living with HIV. HAND symptoms range from subclinical cognitive impairment to dementia; the mechanisms that underlie HAND remain unclear and there is no treatment. The HIV-protein transactivator of transcription (TAT) is thought to contribute to HAND because it persists in the CNS and elicits neurotoxicity in animal models. Network hyperexcitability is associated with accelerated cognitive decline in neurodegenerative disorders. Here, we show that the antiepileptic drug levetiracetam (LEV) attenuated aberrant excitatory synaptic transmission, protected synaptic plasticity, reduced seizure susceptibility, and preserved cognition in inducible TAT (iTAT) transgenic male mice. iTAT mice had an increased frequency of spontaneous excitatory postsynaptic currents in hippocampal slice recordings and impaired long-term potentiation, a form of synaptic plasticity that underlies learning and memory. Two-week administration of LEV by osmotic minipump prevented both impairments. Kainic acid administered to iTAT mice induced a higher maximum behavioral seizure score, longer seizure duration, and a shorter latency to first seizure, consistent with a lower seizure threshold. LEV treatment prevented these in vivo signs of hyperexcitability. Lastly, in the Barnes maze, iTAT mice required more time to reach the goal, committed more errors, and received lower cognitive scores relative to iTAT mice treated with LEV. Thus, TAT expression drives functional deficits, suggesting a causative role in HAND. As LEV not only prevented aberrant synaptic activity in iTAT mice, but also prevented cognitive dysfunction, it may provide a promising pharmacological approach to the treatment of HAND. Significance Statement Around half of people living with HIV also suffer from HIV-associated neurocognitive disorder (HAND), for which there is no treatment. The HIV protein TAT causes toxicity that is thought to contribute to HAND. Here, we show that an antiepileptic drug, levetiracetam (LEV), prevented synaptic and cognitive impairments that develop in a TAT-expressing mouse. LEV is widely used to treat seizures and is well-tolerated in humans, including those with HIV. This study supports further investigation of LEV-treatment for neuroprotection in HAND.

Ustekinumab in paediatric patients with moderately to severely active Crohn's disease: UniStar study long-term extension results.

OBJECTIVES: To assess the efficacy, safety, immunogenicity, and pharmacokinetics through 240 weeks of ustekinumab treatment in paediatric patients from the long-term extension (LTE) of the phase 1, double-blind UniStar trial. METHODS: Paediatric patients with moderately to severely active Crohn's disease (CD) were randomised 1:1 and stratified by body weight (<40 or ≥40 kg) to low- or high-dose intravenous ustekinumab followed by a subcutaneous maintenance dose at Week 8. At Week 16, patients were eligible to enter the LTE at the discretion of the investigator and continued maintenance dosing every 8 weeks up to Week 240. RESULTS: Of the 34 patients who entered the LTE, 25 patients with evaluable data completed Week 48, and 41.2% (14/34) achieved clinical remission at Week 48. Among the 24 patients with Week-0 C-reactive protein (CRP) levels ≥3 mg/L, 29.2% (7/24) achieved normalisation of CRP at Week 48, while imputing missing data as failures. Through Week 240, the most common adverse events were infections (n = 28) and gastrointestinal disorders (n = 26). The most common serious adverse event was worsening of CD (n = 6). Only one patient had detectable antibodies to ustekinumab. Median serum ustekinumab concentrations remained consistent through Week 48, were detectable through Week 224, and trended lower in patients <40 kg. CONCLUSIONS: Efficacy and pharmacokinetics through 1 year and safety and immunogenicity through 4 years of ustekinumab treatment in paediatric patients with CD were generally comparable to those previously reported in adults.

A Scalable Histological Method to Embed and Section Multiple Brains Simultaneously.

The preparation and processing of rodent brains for evaluation by immunohistochemistry is time-consuming. A large number of mouse brains are routinely used in experiments in neuroscience laboratories to evaluate several models of human diseases. Thus, methods are needed to reduce the time associated with processing brains for histology. A scalable method was developed to embed, section, and stain multiple mouse brains using supplies found in any common histology laboratory. Section collection schemes can be scaled to provide identical bregma locations between adjacent sections for immunohistochemistry, facilitating comprehensive, high-quality immunohistochemistry. As a result, sectioning and staining times are considerably reduced as sections from multiple blocks are stained simultaneously. This method improves on previous procedures and allows multiple embedding and subsequent immunostaining of brains easily with a dramatically reduced time requirement. Furthermore, we expand this method for use in numerous mouse tissues, rat brain tissue, and post-mortem human brain and arterial tissues. In summary, this procedure allows the processing of many rodent or human tissues from perfusion through microscopy in 10 days or less.

National Trends in Hospital Performance in Guideline-Recommended Pharmacologic Treatment for Heart Failure at Discharge.

BACKGROUND: The use of recommended heart failure (HF) medications has improved over time, but opportunities for improvement persist among women and at rural hospitals. OBJECTIVES: This study aims to characterize national trends in performance in the use of guideline-recommended pharmacologic treatment for HF at U.S. Department of Veterans Affairs (VA) hospitals, at which medication copayments are modest. METHODS: Among patients discharged from VA hospitals with HF between January 1, 2013, and December 31, 2019, receipt of all guideline-recommended HF pharmacotherapy among eligible patients was assessed, consisting of evidence-based beta-blockers; angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or angiotensin receptor neprilysin inhibitors; mineralocorticoid receptor antagonists; and oral anticoagulation. RESULTS: Of 55,560 patients at 122 hospitals, 32,304 (58.1%) received all guideline-recommended HF medications for which they were eligible. The proportion of patients receiving all recommended medications was higher in 2019 relative to 2013 (OR: 1.54; 95% CI: 1.44-1.65). The median of hospital performance was 59.1% (Q1-Q3: 53.2%-66.2%), improving with substantial variation across sites from 2013 (median 56.4%; Q1-Q3: 50.0%-62.0%) to 2019 (median 65.7%; Q1-Q3: 56.3%-73.5%). Women were less likely to receive recommended therapies than men (adjusted OR [aOR]: 0.84; 95% CI: 0.74-0.96). Compared with non-Hispanic White patients, non-Hispanic Black patients were less likely to receive recommended therapies (aOR: 0.83; 95% CI: 0.79-0.87). Urban hospital location was associated with lower likelihood of medication receipt (aOR: 0.73; 95% CI: 0.59-0.92). CONCLUSIONS: Forty-two percent of patients did not receive all recommended HF medications at discharge, particularly women, minority patients, and those receiving care at urban hospitals. Rates of use increased over time, with variation in performance across hospitals.

Inputs to the locus coeruleus from the periaqueductal gray and rostroventral medulla shape opioid-mediated descending pain modulation.

The supraspinal descending pain modulatory system (DPMS) shapes pain perception via monoaminergic modulation of sensory information in the spinal cord. However, the role and synaptic mechanisms of descending noradrenergic signaling remain unclear. Here, we establish that noradrenergic neurons of the locus coeruleus (LC) are essential for supraspinal opioid antinociception. While much previous work has emphasized the role of descending serotonergic pathways, we find that opioid antinociception is primarily driven by excitatory output from the ventrolateral periaqueductal gray (vlPAG) to the LC. Furthermore, we identify a previously unknown opioid-sensitive inhibitory input from the rostroventromedial medulla (RVM), the suppression of which disinhibits LC neurons to drive spinal noradrenergic antinociception. We describe pain-related activity throughout this circuit and report the presence of prominent bifurcating outputs from the vlPAG to the LC and the RVM. Our findings substantially revise current models of the DPMS and establish a supraspinal antinociceptive pathway that may contribute to multiple forms of descending pain modulation.

Mass Participation and Tournament Event Management for the Team Physician: A Consensus Statement (2022 Update).

ABSTRACT: Mass participation events include endurance events (e.g., marathon, triathlon) and/or competitive tournaments (e.g., baseball, tennis, football (soccer) tournaments). Event management requires medical administrative and participant care planning. Medical management provides safety advice and care at the event that accounts for large numbers of participants, anticipated injury and illness, variable environment, repeated games or matches, and mixed age groups of varying athletic ability. This document does not pertain to the care of the spectator.

A Novel Approach to Shaping the Lateral Abdomen: Simultaneous Application of High-Intensity Focused Electromagnetic (HIFEM) Therapy and Synchronized Radiofrequency at the Flanks: A Multicenter MRI Study.

BACKGROUND: An accumulation of adipose tissue on the lateral abdomen (flanks) coupled with muscle deconditioning negatively affects core stability, muscular balance, and the intrinsic strength essential for maintaining optimal body mechanics and posture. This lateral fat accumulation and diminution of muscle result in an unfavorable abdominal profile and present challenges in finding appropriately fitting attire. OBJECTIVES: The aim of this study was to explore the effectiveness and safety of the simultaneous application of high-intensity focused electromagnetic (HIFEM) therapy and synchronized radiofrequency for sculpting the lateral abdomen. METHODS: All patients were scheduled to undergo four 30-minute treatments at approximately weekly intervals and then subsequent follow-up visits at 1 month and 3 months after the last treatment. The primary evaluation assessed changes in the oblique muscles, adipose tissue thickness, and cross-sectional area (CSA) by MRI performed at baseline and follow-ups. The secondary outcomes included digital photographs of the treated areas, a Subject Satisfaction Questionnaire, and a Therapy Comfort Questionnaire. Adverse events and side effects were monitored throughout the study duration. RESULTS: The muscle tissue showed a substantial increase in thickness (+27.2%) and CSA (+29.0%). The adipose tissue measurements showed a decrease of -30.5% in CSA and -28.8% in thickness. As secondary outcomes, 81.8% of patients reported feeling more toned, and 84.9% of patients found the treatment comfortable and reported less than mild pain. CONCLUSIONS: Based on the evaluation, the study suggests that the simultaneous application of HIFEM and synchronized radiofrequency is safe and effective for reducing adipose tissue and strengthening muscle in the area of the lateral abdomen.

Mass Participation and Tournament Event Management for the Team Physician: A Consensus Statement (2022 Update).

ABSTRACT: Mass participation events include endurance events (e.g., marathon, triathlon) and/or competitive tournaments (e.g., baseball, tennis, football (soccer) tournaments). Event management requires medical administrative and participant care planning. Medical management provides safety advice and care at the event that accounts for large numbers of participants, anticipated injury and illness, variable environment, repeated games or matches, and mixed age groups of varying athletic ability. This document does not pertain to the care of the spectator.

Initial Assessment and Management of Select Musculoskeletal Injuries: A Team Physician Consensus Statement.

ABSTRACT: Musculoskeletal injuries occur frequently in sport during practice, training, and competition. Injury assessment and management are common responsibilities for the team physician. Initial Assessment and Management of Musculoskeletal Injury-A Team Physician Consensus Statement is title 23 in a series of annual consensus documents written for the practicing team physician. This statement was developed by the Team Physician Consensus Conference, an annual project-based alliance of six major professional associations. The goal of this document is to help the team physician improve the care and treatment of the athlete by understanding the initial assessment and management of selected musculoskeletal injuries.

Antiretroviral drugs from multiple classes induce loss of excitatory synapses between hippocampal neurons in culture.

Introduction: Antiretroviral (ARV) drugs have improved prognoses for people living with HIV. However, HIV-associated neurocognitive disorders (HAND) persist despite undetectable viral loads. Some ARVs have been linked to neuropsychiatric effects that may contribute to HAND. Synapse loss correlates with cognitive decline in HAND and synaptic deficits may contribute to the neuropsychiatric effects of ARV drugs. Methods: Using an automated high content assay, rat hippocampal neurons in culture expressing PSD95-eGFP to label glutamatergic synapses and mCherry to fill neuronal structures were imaged before and after treatment with 25 clinically used ARVs. Results and Discussion: At a concentration of 10 µM the protease inhibitors nelfinavir and saquinavir, the non-nucleoside reverse transcriptase inhibitors etravirine and the 8-OH metabolite of efavirenz, the integrase inhibitor bictegravir, and the capsid inhibitor lenacapavir produced synaptic toxicity. Only lenacapavir produced synapse loss at the nanomolar concentrations estimated free in the plasma, although all 4 ARV drugs induced synapse loss at Cmax. Evaluation of combination therapies did not reveal synergistic synaptic toxicity. Synapse loss developed fully by 24 h and persisted for at least 3 days. Bictegravir-induced synapse loss required activation of voltage-gated Ca2+ channels and bictegravir, etravirine, and lenacapavir produced synapse loss by an excitotoxic mechanism. These results indicate that select ARV drugs might contribute to neuropsychiatric effects in combination with drugs that bind serum proteins or in disease states in which synaptic function is altered. The high content imaging assay used here provides an efficient means to evaluate new drugs and drug combinations for potential CNS toxicity.

Can an effective end-of-life intervention for advanced dementia be viewed as moral?

Many people dread prolonged dying with suffering in the terminal illness, advanced dementia. To successfully facilitate a timely dying, advance directives must be effective and acceptable. This article considers whether authorities, including treating physicians, can accept as moral, the effective intervention that ceases caregivers' assistance with oral feeding and hydrating. The article presents eight criticisms and "alternate views" regarding ceasing assisted feeding/hydrating. It draws on perspectives from clinical medicine, law, ethics, and religion. The conflict is between (A) people's core beliefs that reflect cultural norms and religious teachings regarding what is moral versus (B) patients' autonomous right of self-determination and claim right to avoid suffering. The article presents each side as strongly as possible. Accepting the intervention as moral could allow patients a peaceful and timely dying from patients' underlying disease. Confidence in future success can deter patients and their surrogates from considering a hastened dying in earlier stages of dementia.

Timely dying in dementia: Use patients' judgments and broaden the concept of suffering.

Patients living with advanced dementia (PLADs) face several challenges to attain the goal of avoiding prolonged dying with severe suffering. One is how to determine when PLADs' current suffering becomes severe enough to cease all life-sustaining treatments, including withdrawing assistance with oral feeding and hydrating, a controversial order. This article broadens the concept of suffering by including suffering that cannot be observed contemporaneously and the suffering of loved ones. Four paradigm shifts operationalize these concepts. During advance care planning, patients can judge which future clinical conditions would cause severe suffering. To decide when to allow patients to die, treating physicians/providers only need to assess if patients have reached patients' previously judged, qualifying conditions. Questions: Will this protocol prevent PLADs' prolonged dying with suffering? Deter early-stage dementia patients from committing preemptive suicide? Sway decision-making surrogates from withholding life-sustaining treatments from patients with middle-stage dementia? Provoke providers' resistance to relinquish their traditional, unilateral authority to determine patients' suffering?

Cryoballoon ablation for atrial fibrillation in South Africa: One-year outcome from the Cryo Global Registry.

BACKGROUND: Pulmonary vein isolation (PVI) with cryoballoon catheter ablation (CBA) is a well-established and widely adopted method for the treatment of patients with atrial fibrillation (AF) to prevent recurrences of AF. CBA adoption in South Africa (SA) and outcome data in SA patients are limited. OBJECTIVES: To evaluate real-world usage, safety and effectiveness of CBA in SA. METHODS: In this sub-analysis of the Cryo Global Registry, 81 participants with paroxysmal AF (PAF) and persistent AF (PsAF) were enrolled between 2017 and 2021 across two private SA hospitals. Baseline characteristics, procedural characteristics, 12-month safety, effectiveness (atrial arrhythmia recurrence), healthcare utilisation (repeat ablation and all-cause hospitalisation), quality of life (QoL; measured by EQ-5D-3L) and predefined symptoms were reported on. RESULTS: Participants in the SA cohort were a mean (standard deviation) of 60 (12) years old, 19 (23.5%) were female, and 48 (59.3%) presented with PAF. The overall presence of baseline comorbidities in the SA cohort was relatively low compared with the entire Cryo Global Registry cohort. The acute PVI success rate was high (98.8%). Two serious procedure-related adverse events occurred in 2 (2.5%) participants in the SA cohort. Freedom from arrhythmia recurrence was 97.4% (95% confidence interval (CI) 83.2 - 99.6%) in PAF and 78.4% (95% CI 58.1 - 89.7%) in persistent AF (p=0.035). Kaplan-Meier estimates for freedom from repeat ablations and all-cause hospitalisations were 97.0% (95% CI 88.4 - 99.2%) and 98.5% (95% CI 90.0 - 99.8%), respectively. Participants reported significant improvement in EQ-5D-3L index score and symptoms from baseline (0.90 (0.11)) - 12 months (0.97 (0.07), p<0.001). CONCLUSION: CBA standard-of-care procedures in SA resulted in a high clinical freedom from arrhythmia recurrence, with a low risk of safety events within 12 months post ablation. In addition, participants experienced an improvement in QoL and high freedom from healthcare utilisation at 12 months. The obtained results will be important for guiding clinical decisions around CBA in SA.