Developmental and genomic insight into the origin of the tardigrade body plan.

Tardigrada is an ancient lineage of miniaturized animals. As an outgroup of the well-studied Arthropoda and Onychophora, studies of tardigrades hold the potential to reveal important insights into body plan evolution in Panarthropoda. Previous studies have revealed interesting facets of tardigrade development and genomics that suggest that a highly compact body plan is a derived condition of this lineage, rather than it representing an ancestral state of Panarthropoda. This conclusion was based on studies of several species from Eutardigrada. We review these studies and expand on them by analyzing the publicly available genome and transcriptome assemblies of Echiniscus testudo, a representative of Heterotardigrada. These new analyses allow us to phylogenetically reconstruct important features of genome evolution in Tardigrada. We use available data from tardigrades to interrogate several recent models of body plan evolution in Panarthropoda. Although anterior segments of panarthropods are highly diverse in terms of anatomy and development, both within individuals and between species, we conclude that a simple one-to-one alignment of anterior segments across Panarthropoda is the best available model of segmental homology. In addition to providing important insight into body plan diversification within Panarthropoda, we speculate that studies of tardigrades may reveal generalizable pathways to miniaturization.

Patterns of peripheral neuropathy in ART-naïve patients initiating modern ART regimen.

The purpose of this study was to evaluate associations of pre-ART CD4 with peripheral neuropathy (PN) and estimate the prevalence of PN in HIV-positive patients starting modern combination antiretroviral therapy (cART) regimens. ART-naïve subjects initiating cART were followed longitudinally and screened for signs/symptoms of PN. Lower pre-ART CD4 count was associated with post-ART PN. After 7 years (n = 117), the prevalence (95% CI) of PN and SPN were 31% (23, 40%) and 5% (2, 11%) with pre-ART CD4 count >250 copies/µL. PN continues to be identified in HIV-infected individuals on modern cART by targeted assessment but is generally without symptoms.

Experience and challenges presented by a multicenter crossover study of combination analgesic therapy for the treatment of painful HIV-associated polyneuropathies.

OBJECTIVE: There is limited evidence for efficacy of analgesics as monotherapy for neuropathic pain associated with HIV-associated polyneuropathies, in spite of demonstrated efficacy in other neuropathic pain conditions. We evaluated the tolerability and analgesic efficacy of duloxetine, methadone, and the combination of duloxetine-methadone compared with placebo. DESIGN: This study was a phase II, randomized, double-blind, placebo-controlled, four-period crossover multicenter study of analgesic therapy for patients with at least moderate neuropathic pain due to HIV-associated polyneuropathy. Duloxetine, methadone, combination duloxetine-methadone, and placebo were administered in four different possible sequences. The primary outcome measure was mean pain intensity (MPI) measured daily in a study-supplied pain diary. RESULTS: A total of 15 patients were enrolled from eight study sites and eight patients completed the entire trial. Study treatments failed to show statistically significant change in MPI compared with placebo. Adverse events were frequent and associated with high rates of drug discontinuation and study dropout. CONCLUSIONS: Challenges with participant recruitment and poor retention precluded trial completion to its planned targets, limiting our evaluation of the analgesic efficacy of the study treatments. Challenges to successful completion of this study and lessons learned are discussed.

Article Topic: Neuropathies Due to Infections and Antimicrobial Treatments.

Purpose of eview: The aim of this review is to discuss the presentation, diagnosis, and management of polyneuropathy (PN) in selected infections. Overall, most infection related PNs are an indirect consequence of immune activation rather than a direct result of peripheral nerve infection,  Schwann cell infection, or toxin production, though note this review will describe infections that cause PN through all these mechanisms. Rather than dividing them by each infectious agent separately, we have grouped the infectious neuropathies according to their presenting phenotype, to serve as a guide to clinicians. Finally, toxic neuropathies related to antimicrobials are briefly summarized. Recent findings: While PN from many infections is decreasing, increasing evidence links infections to variants of GBS. Incidence of neuropathies secondary to use of HIV therapy has decreased over the last few years. Summary: In this manuscript, a general overview of the more common infectious causes of PN will be discussed, dividing them across clinical phenotypes: large- and small-fiber polyneuropathy, Guillain-Barré syndrome (GBS), mononeuritis multiplex, and autonomic neuropathy. Rare but important infectious causes are also discussed.

Digital Solutions Observed in Clinical Trials: A Formative Feasibility Scoping Review.

Growing digital access accelerates digital transformation of clinical trials where digital solutions (DSs) are increasingly and widely leveraged for improving trial efficiency, effectiveness, and accessibility. Many factors impact DS success including technology barriers, privacy concerns, or user engagement activities. It is unclear how those factors are considered or reported in the literature. Here, we perform a formative feasibility scoping review to identify gaps impacting DS quality and reproducibility in trials. Articles containing digital terms published in English from 2009 to 2022 were collected (n=4,167). 130 articles published between 2016 and 2022 were randomly selected for full-text review. Eligible articles (n=100) were sorted into four identified categories: 16% Education, 59% Intervention, 8% Patient, 17% Treatment. Initial findings about DS trends and reporting practices inform protocol development for a large-scale study urging the generation of fundamental knowledge on reporting standardization, best practice guidelines, and evaluation methodologies related to DS for clinical trials.

Tofacitinib-induced Progressive Multifocal Leukoencephalopathy with Immune Reconstitution Inflammatory Syndrome.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) with subsequent immune reconstitution inflammatory syndrome (IRIS) is a rare disease associated with compromised immune systems. It has never been described in a patient taking tofacitinib. CASE PRESENTATION: A 49-year-old woman with history of systemic lupus erythematous treated with tofacitinib presented with several weeks of intermittent fevers and altered mental status. MRI revealed multifocal T2-weighted FLAIR hyperintensities in the subcortical white matter, including the subcortical U-fibers, without mass effect or contrast enhancement, compatible with PML. Tofacitinib was stopped and the patient's symptoms initially improved. However, the patient presented again less than a week after discharge with three days of left arm weakness, left facial droop, dysarthria, and one day of confusion. Repeat MRI demonstrated interval progression in T2/FLAIR hyperintensities with development of patchy gadolinium enhancement on T1-post contrasted sequences, consistent with development of IRIS in the setting of tofacitinib cessation. DISCUSSION: This is the first case describing PML-IRIS in the setting of administration and subsequent cessation of tofacitinib.

The effects of differing nutritional levels and body condition score on scrotal circumference, motility, and morphology of bovine sperm.

Bulls often experience various levels of nutrient availability throughout the year. Nutritional management is a critical factor on overall ejaculate composition and the ability to get females pregnant. We hypothesized that differing nutritional levels and body condition score (BCS) affect reproductive fertility parameters in bulls. Mature Angus bulls (n = 11) were individually housed and randomly assigned to one of two dietary regimens: 1) over-fed (n = 5) or 2) restricted (n = 6). Bulls were fed the same ration at different volumes to achieve desired effects resulting in eight individual treatments: gain to an over-fed body condition score ([BCS]; GO), gain after nutrient restriction (GR), loss after an over-fed BCS (LO), loss from nutrient restriction (LR), maintenance at ideal adiposity (BCS = 6) after overfeeding (IMO), maintenance at ideal adiposity after nutrient restriction (IMR), maintenance at an over-fed BCS (BCS = 8; MO), and maintenance at a restricted BCS (BCS = 4; MR). Body weight (BW) and BCS were recorded every 2 wk to monitor bull weight and BCS changes. Scrotal circumference was measured every 28 d. Body fat and sperm motility and morphology were evaluated every 84 d. Scrotal circumference, motility, and morphology were normalized to the initial value of each bull. Thus, allowing the individual bull to serve as a control. Statistical analyses were conducted with PROC GLIMMIX of SAS as a complete randomized design to determine if treatment influenced BW, BCS, scrotal circumference, motility, morphology, and adipose thickness. Scrotal circumference (P < 0.001) had the least amount of deviation from initial during the LR (0.29 ±â€…0.44) treatment and the greatest during the MO (3.06 ±â€…0.44), LO (2.28 ±â€…0.44), MR (2.43 ±â€…0.44), GR (3.03 ±â€…0.44), and IMR (2.91 ±â€…0.44) treatments. Sperm motility was not affected by nutritional treatments (P = 0.55). Both head and total defects of sperm differed (P = 0.02) due to nutritional treatments. Increased head abnormalities occurred during the LO (37.60 ±â€…8.61) treatment, with no differences between the other treatments. Total defects increased during the LO (43.80 ±â€…9.55) treatment with similar increases in bulls during the GR (29.40 ±â€…9.55) and IMR (35.60 ±â€…9.55) treatments. In conclusion, male fertility was impacted when a deviation from a BCS of 6 occurred which could be detrimental to reproductive and beef production efficiency.

Electrodiagnostic Assessment of Hyperexcitable Nerve Disorders.

Peripheral nerve hyperexcitability (PNH) typically presents with complaints of muscle twitching, cramps, and muscle stiffness. Symptoms and signs indicating central and/or autonomic nervous system dysfunction also may be reported. An electroclinical spectrum exists, spanning from the milder cramp-fasciculation syndrome to more severe syndromes characterized by continuous muscle fiber activity. It is important to recognize that PNH may be an autoimmune phenomenon associated with antibodies targeting proteins of the voltage-gated potassium channel-complex and, in some patients, a paraneoplastic phenomenon. Symptomatic therapies include medicines that reduce neuronal excitability and in severe disease immunomodulatory treatments may be indicated.

The effects of protein level on cytokines and chemokines in the uterine environment of beef heifers during development.

The development of replacement heifers is crucial for breeding success and herd efficiency. Nutritional management can affect not only reproductive development but also the inflammatory status of the uterine environment, which may impact reproductive functions such as pregnancy establishment and development. The study herein evaluated the concentration of cytokines and chemokines in the uterus of heifers supplemented with different levels of protein. Angus heifers (n = 60) were blocked by body weight (BW) and randomly assigned to 1 of 3 treatments based on protein supplementation level: control of 10% crude protein (CON), 20% crude protein (P20), or 40% crude protein (P40). BW, body condition score, and blood samples were taken every 2 wk for 140 d to monitor development. Uterine flushes were performed monthly and concentrations of cytokines (IL-1α, IL-1ß, TNF-α, IFN-γ, IL-10, VEGF-α, IL-17A, and IL-36RA) and chemokines (IL-8, MCP-1, MIP-1α, and MIP-1ß) were quantified via ELISA multiplex. To test if there were mean differences in cytokines between the treatment groups or over time, PROC GLIMMIX (SAS v 9.4) was utilized. Concentrations of all cytokines and chemokines, except IL-1α, changed throughout heifer development (P < 0.05). Heifers in the P40 treatment group displayed reduced concentrations of MCP-1 (P = 0.007) and tended to have decreased concentrations of IFN-γ (P = 0.06). Cytokine IL-36RA tended (P = 0.06) to be affected by protein level, with the lowest concentrations observed in CON heifers. Most cytokines and chemokines increased following the initial month of supplementation (P < 0.05). The increase in concentrations after 1 mo may indicate an adaptive response in the uterus to diet change. Cytokines and chemokines fluctuated due to physiological changes occurring during development. Further research is needed to determine the influence of nutrition on uterine inflammation and long-term impacts on reproductive function.

HIV neuropathy in South Africans: frequency, characteristics, and risk factors.

The purpose was to estimate the frequency, characteristics, and risk factors of HIV-associated distal sensory polyneuropathy (DSP) among South Africans who attend an urban community-based clinic. In a cross-sectional study, neuropathy status was determined in 598 HIV-infected adults using validated tools (Brief Peripheral Neuropathy Screen and a modified version of the Total Neuropathy Score) to categorize subjects as DSP versus no DSP. Symptomatic DSP (SDSP) required the presence of at least two neuropathic signs together with symptoms. Clinical, anthropometric, and laboratory evaluations were prospectively performed. CD4 counts, antiretroviral therapy (ART), and questionnaires regarding previous tuberculosis (TB) and alcohol exposure were collected retrospectively. Approximately half (49%) of the study population were diagnosed with DSP, and 30% of the study population were diagnosed with SDSP. In multivariate analyses the odds ratio (OR) (95% confidence interval) of DSP were independently associated with ART use (OR 1.7, 1.0-2.9), age (per 10 year increment) (OR 1.7, 1.4-2.2), and prior TB (OR 2.0, 1.3-3.0). Pain or paresthesias were reported as moderately severe by 70% of those with SDSP. Stavudine use was significantly associated with DSP. DSP is a clinically significant problem in urban HIV-infected Africans. Our findings raise the possibility that the incidence of DSP may be reduced with avoidance of stavudine-containing regimens in older subjects, especially with a history of prior TB infection.

Mechanisms of neuromuscular dysfunction in critical illness.

The development of neuromuscular dysfunction (NMD) during critical illness is increasingly recognized as a cause of failure to wean from mechanical ventilation and is associated with significant morbidity and mortality. At times, it is difficult to identify the presence of NMD and distinguish the etiology of the weakness in patients with critical illness, but subtle clinical findings and bedside electrophysiologic testing are helpful in establishing the diagnosis. This article describes the clinical spectrum of acquired neuromuscular weakness in the setting of critical illness, provides an approach to diagnosis, and discusses its pathogenesis. Finally, a defective sodium channel regulation as a unifying mechanism underlying NMD in critically ill patients is proposed.

Update of HIV-Associated Sensory Neuropathies.

PURPOSE OF REVIEW: HIV-sensory neuropathy (HIV-SN) remains a common complication of HIV infection and may be associated with significant morbidity due to neuropathic pain. The overall purpose of this review is to discuss trends in the changing epidemiology in HIV-SN, new data regarding the pathophysiology of the condition, and discuss approaches to management. RECENT FINDINGS: While HIV-SN has been historically considered the most common neurological complication of HIV infection, improved accessibility to effective combination antiretroviral therapy (cART), use of less neurotoxic antiretroviral medication regimens, and trends towards earlier introduction of treatment have impacted the condition: overall incident HIV-SN is likely decreased compared to prior rates and patients afflicted by HIV-SN may more frequently have asymptomatic or subclinical disease. Traditional predictors of HIV-SN have also changed, as traditional indices of severe immune deficiency such as low CD4 count and high viral load no longer predict HIV-SN. Emerging evidence supports the contention that both peripheral and central mechanisms underlying the generation as well as persistence of neuropathic pain in HIV-SN exist. It is important to recognize that even mild neuropathic pain in this clinical population is associated with meaningful impairment in quality of life and function, which emphasizes the clinical importance of recognizing and treating the condition. The general approach to management of neuropathic pain in HIV-SN is the introduction of symptomatic analgesic therapy. There exist, however, few evidence-based analgesic options for HIV-SN based on available clinical data. Symptomatic treatment trials are increasingly recognized to have been potentially confounded by more robust placebo response than that observed in other neuropathic pain conditions. In the authors' experience, use of analgesic therapies with proven efficacy in other neuropathic pain conditions is appropriate, bearing in consideration potential pharmacokinetic interactions with the cART regimen. Combination analgesic regimens may also achieve meaningful analgesic responses, particularly when drugs with differing mechanisms of action are utilized. It is paramount that the patient is appropriately counseled regarding expectations and the anticipated benefit of analgesic therapy, as pain relief is often incomplete but clinically meaningful improvement in pain and function can be achieved.

A dangerous dilemma: management of infectious intracranial aneurysms complicating endocarditis.

A 41-year-old right-handed man with bicuspid aortic valve and a 3-month history of chronic fever and weight loss presented with sudden onset of severe headache. Computerised tomography of the head revealed a right basal ganglia haemorrhage. Further investigation documented Streptococcus mitis bacteraemia, a fusiform right middle cerebral artery aneurysm, and an abscess at the base of the anterior leaflet of the mitral valve. The patient subsequently died when repeat aneurysmal haemorrhage resulted in cerebral herniation and brain death while on antibiotic therapy. Infectious intracranial aneurysms (IIAs) are uncommon but severe complications of bacterial endocarditis. Several case series have been published evaluating the management of IIAs, but no randomised controlled trials exist to guide treatment decisions. Improved diagnostic techniques, microvascular neurosurgical approaches, and endovascular therapies hold the promise of improved outcomes in the future. This difficult case is used to show an approach towards the management of IIAs complicating bacterial endocarditis based on a review of the published work.

The Myotonic Plot Thickens: Electrical Myotonia in Antimuscle-Specific Kinase Myasthenia Gravis.

Electrical myotonia is known to occur in a number of inherited and acquired disorders including myotonic dystrophies, channelopathies, and metabolic, toxic, and inflammatory myopathies. Yet, electrical myotonia in myasthenia gravis associated with antibodies against muscle-specific tyrosine kinase (MuSK) has not been previously reported. We describe two such patients, both of whom had a typical presentation of proximal muscle weakness with respiratory failure in the context of a significant electrodecrement in repetitive nerve stimulation. In both cases, concentric needle examination revealed electrical myotonia combined with myopathic motor unit morphology and early recruitment. These findings suggest that MuSK myasthenia should be included within the differential diagnosis of disorders with electrical myotonia.

Neuromuscular manifestations of HIV/AIDS.

The human immunodeficiency virus (HIV) epidemic, now entering its fourth decade, affects approximately 33 million people living in both developed and resource-limited countries. Neurological complications of the peripheral nervous system are common in HIV-infected patients, and neuromuscular pathology is associated with significant morbidity. Peripheral neuropathy is the most common neuromuscular manifestation observed in HIV/AIDS, and in the antiretroviral era, its prevalence has increased. The purpose of this review was to describe the clinical spectrum of neuromuscular disorders in the setting of HIV infection and to provide an approach to diagnosis and management.