Development of PCR-Multiplex Assays for Identification of the Herpotrichiellaceae Family and Agents Causing Chromoblastomycosis.

The Herpotrichiellaceae family is an important group of dematiaceous filamentous fungi, associated with a variety of pathogenic fungal species causing chromoblastomycosis (CBM) and phaeohyphomycosis (PHM), both with polymorphic clinical manifestations and worldwide incidence. Currently, the identification of this family and determination of the causative agent is challenging due to the subjectivity of morphological identification methods, necessitating the use of molecular techniques to complement diagnosis. In this context, genetic sequencing of the Internal Transcribed Spacer (ITS) has become the norm due to a lack of alternative molecular tools for identifying these agents. Therefore, this study aimed to develop PCR-Multiplex methodologies to address this gap. Sequences from the ITS and Large Subunit (LSU) of ribosomal DNA were used, and after manual curation and in vitro analyses, primers were synthesized for the identification of the targets. The primers were optimized and validated in vitro, resulting in two PCR-Multiplex methodologies: one for identifying the Herpotrichiellaceae family and the bantiana clade, and another for determining the species Fonsecaea pedrosoi and Fonsecaea monophora. Ultimately, the assays developed in this study aim to complement other identification approaches for these agents, reducing the need for sequencing, improving the management of these infections, and enhancing the accuracy of epidemiological information.

Persistent inward currents in human motoneurons: Emerging evidence and future directions.

The manner in which motoneurons respond to excitatory and inhibitory inputs depends strongly on how their intrinsic properties are influenced by the neuromodulators serotonin and noradrenaline. These neuromodulators enhance the activation of voltage­gated channels that generate persistent (long-lasting) inward sodium and calcium currents (PICs) into the motoneurons. PICs are crucial for initiating, accelerating, and maintaining motoneuron firing. A greater accessibility to state-of-the-art techniques that allows both the estimation and examination of PIC modulation in tens of motoneurons in vivo has rapidly evolved our knowledge of how motoneurons amplify and prolong the effects of synaptic input. We are now in a position to gain substantial mechanistic insight into the role of PICs in motor control at an unprecedented pace. The present review briefly describes the effects of PICs on motoneuron firing and the methods available for estimating them before presenting the emerging evidence of how PICs can be modulated in health and disease. Our rapidly developing knowledge of the potent effects of PICs on motoneuron firing has the potential to improve our understanding of how we move, and points to new approaches to improve motor control. Finally, gaps in our understanding are highlighted and methodological advancements suggested to encourage readers to explore outstanding questions to further elucidate PIC physiology.

Effect of Ubrogepant on Patient-Reported Outcomes When Administered During the Migraine Prodrome: Results From the Randomized PRODROME Trial.

BACKGROUND AND OBJECTIVES: Ubrogepant is a calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine. The PRODROME trial previously demonstrated that ubrogepant treatment during prodrome prevents the onset of moderate or severe headache. In this analysis of the PRODROME trial, the benefits of ubrogepant treatment during the prodrome on patient-reported outcomes (PROs) are evaluated. METHODS: PRODROME was a multicenter, randomized, double-blind, placebo-controlled, crossover trial that enrolled adults who experienced 2-8 migraine attacks per month with moderate-severe headache pain. Eligible participants treated 2 qualifying prodrome events, defined as a migraine attack with prodromal symptoms when the participant was confident a headache would follow within 1-6 hours. Participants were randomized to treatment sequence A (placebo then ubrogepant 100 mg) or sequence B (ubrogepant 100 mg then placebo). This analysis evaluated the ability to function normally over 24 hours (secondary end point) and at specific time points after dose (additional end point). Other PRO end points included activity limitation over 24 hours and satisfaction with study medication at 8 and 24 hours. RESULTS: Of 518 randomized participants, 477 comprised the modified intent-to-treat population. After treatment of qualifying prodrome events, a significantly greater ability to function normally over 24 hours was observed for participants after treatment with ubrogepant 100 mg compared with placebo (odds ratio [OR] 1.66, 95% CI 1.40-1.96; p < 0.0001). As early as 2 hours after dose, a greater proportion of ubrogepant-treated participants reported "no disability, able to function normally" compared with placebo (OR 1.76, 95% CI 1.32-2.35; nominal p = 0.0001). Ubrogepant administered during the prodrome was also associated with a greater reduction in activity limitations over 24 hours after dose (OR 2.07, 95% CI 1.61-2.67; nominal p < 0.0001). At 8 and 24 hours after dose, rates of being "satisfied" or "extremely satisfied" were greater for ubrogepant than for placebo (8 hours: OR 2.37, 95% CI 1.78-3.15; nominal p < 0.0001; 24 hours: OR 2.32, 95% CI 1.78-3.02; nominal p < 0.0001). DISCUSSION: Ubrogepant 100 mg administered during the prodrome was associated with significantly greater ability to function normally, greater reduction in activity limitations over 24 hours, and greater satisfaction with study medication, compared with placebo. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT04492020. Submitted: July 27, 2020; first patient enrolled: August 21, 2020. clinicaltrials.gov/ct2/show/NCT04492020. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that taking ubrogepant 100 mg during a migraine prodrome allows more patients to function normally over the next 24 hours.

Synonymous codon substitutions modulate transcription and translation of a divergent upstream gene by modulating antisense RNA production.

Synonymous codons were originally viewed as interchangeable, with no phenotypic consequences. However, substantial evidence has now demonstrated that synonymous substitutions can perturb a variety of gene expression and protein homeostasis mechanisms, including translational efficiency, translational fidelity, and cotranslational folding of the encoded protein. To date, most studies of synonymous codon-derived perturbations have focused on effects within a single gene. Here, we show that synonymous codon substitutions made far within the coding sequence of Escherichia coli plasmid-encoded chloramphenicol acetyltransferase (cat) can significantly increase expression of the divergent upstream tetracycline resistance gene, tetR. In four out of nine synonymously recoded cat sequences tested, expression of the upstream tetR gene was significantly elevated due to transcription of a long antisense RNA (asRNA) originating from a transcription start site within cat. Surprisingly, transcription of this asRNA readily bypassed the native tet transcriptional repression mechanism. Even more surprisingly, accumulation of the TetR protein correlated with the level of asRNA, rather than total tetR RNA. These effects of synonymous codon substitutions on transcription and translation of a neighboring gene suggest that synonymous codon usage in bacteria may be under selection to both preserve the amino acid sequence of the encoded gene and avoid DNA sequence elements that can significantly perturb expression of neighboring genes. Avoiding such sequences may be especially important in plasmids and prokaryotic genomes, where genes and regulatory elements are often densely packed. Similar considerations may apply to the design of genetic circuits for synthetic biology applications.

Metabolomics Unveils Disrupted Pathways in Parkinson's Disease: Toward Biomarker-Based Diagnosis.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by diverse symptoms, where accurate diagnosis remains challenging. Traditional clinical observation methods often result in misdiagnosis, highlighting the need for biomarker-based diagnostic approaches. This study utilizes ultraperformance liquid chromatography coupled to an electrospray ionization source and quadrupole time-of-flight untargeted metabolomics combined with biochemometrics to identify novel serum biomarkers for PD. Analyzing a Brazilian cohort of serum samples from 39 PD patients and 15 healthy controls, we identified 15 metabolites significantly associated with PD, with 11 reported as potential biomarkers for the first time. Key disrupted metabolic pathways include caffeine metabolism, arachidonic acid metabolism, and primary bile acid biosynthesis. Our machine learning model demonstrated high accuracy, with the Rotation Forest boosting model achieving 94.1% accuracy in distinguishing PD patients from controls. It is based on three new PD biomarkers (downregulated: 1-lyso-2-arachidonoyl-phosphatidate and hypoxanthine and upregulated: ferulic acid) and surpasses the general 80% diagnostic accuracy obtained from initial clinical evaluations conducted by specialists. Besides, this machine learning model based on a decision tree allowed for visual and easy interpretability of affected metabolites in PD patients. These findings could improve the detection and monitoring of PD, paving the way for more precise diagnostics and therapeutic interventions. Our research emphasizes the critical role of metabolomics and machine learning in advancing our understanding of the chemical profile of neurodegenerative diseases.

Characterization of novel double-reporter strains of Mycobacterium abscessus for drug discovery: a study in mScarlet.

Mycobacterium abscessus (Mab) is an emerging pathogen that poses a severe health threat, especially in people with cystic fibrosis and other chronic lung diseases. Available drugs are largely ineffective due to an exquisite intrinsic resistance, making Mab infections only comparable to multidrug-resistant tuberculosis. Current treatment is based on lengthy multidrug therapy, complicated by poor outcomes and high rates of treatment failure, recurrence, and mortality. Thus, finding new and more efficient drugs to combat this pathogen is urgent. However, drug discovery efforts targeting Mab have been limited, and traditional drug screening methods are labor-intensive, low-throughput, and do not reflect clinical effectiveness. Therefore, this work aimed to develop a new, efficient, and reliable tool for drug screening against Mab that can be used in vitro for identifying hits in a high-throughput manner and in vivo to select drug candidates for future clinical trials. We engineered two stable double-reporter strains of Mab capable of emitting strong fluorescent and luminescent signals. This is due to the expression of mScarlet protein and luciferase enzyme or the entire lux operon. Importantly, these strains maintain the same ground characteristics as the non-transformed Mab strain. We show that these new strains can be applied to various setups, from MIC determination in broth cultures and macrophage infection assays to in vivo infection (using the Galleria mellonella model). Using these strains enhances the potential for high-throughput screening of thousands of compounds in a fast and reliable way. IMPORTANCE: Mycobacterium abscessus (Mab) is currently considered an "incurable nightmare." Its intrinsic resistance, high toxicity, long duration, and low cure rates of available therapies often lead to the clinical decision not to treat. Moreover, one of the significant drawbacks of anti-Mab drug development is the lack of correlation between in vitro susceptibility and clinical efficacy. Most drug screening assays are performed on Mab growing in liquid cultures. But being an intracellular pathogen, inducing granulomas and biofilm formation, the broth culture is far from ideal as in vitro drug-testing setup. This study presents new double-reporter Mab strains that allow direct real-time bacterial detection and quantification in a non-invasive way. These strains can be applied to an extensive range of experimental settings, far surpassing the utility of single-reporter bacteria. They can be used in all steps of the pre-clinical anti-Mab drug development pipeline, constituting a highly valuable tool to increase its success.

Freshwater fish and the Cretaceous/Palaeogene boundary: a critical assessment of survivorship patterns.

Mass extinctions are major influences on both the phylogenetic structure of the modern biota and our ability to reconstruct broad-based patterns of evolutionary history. The most recent mass extinction is also the most famous-that which implicates a bolide impact in defining the Cretaceous/Palaeogene boundary (K/Pg). Although the biotic effects of this event receive intensive scrutiny, certain ecologically important and diverse groups remain woefully understudied. One such group is the freshwater ray-finned fishes (Actinopterygii). These fish represent 25% of modern vertebrate diversity, yet the isolated and fragmentary nature of their K/Pg fossil record limits our understanding of their diversity dynamics across this event. Here, we address this problem using diversification analysis of molecular-based phylogenies alongside a morphotype analysis of fossils recovered from a unique site in the Denver Basin of western North America that provides unprecedented K/Pg resolution. Our results reveal previously unrecognized signals of post-K/Pg diversification in freshwater clades and suggest that the change was driven by localized and sporadic patterns of extinction. Supported inferences regarding the effects of the K/Pg event on freshwater fish also inform our expectations of how freshwater faunas might recover from the current biodiversity crisis.

Abatacept inhibits Th17 differentiation and mitigates α-synuclein-induced dopaminergic dysfunction in mice.

Parkinson's disease (PD) is a multifaceted disease characterized by degeneration of nigrostriatal dopaminergic neurons, which results in motor and non-motor dysfunctions. Accumulation of α-synuclein (αSYN) in Lewy bodies is a key pathological feature of PD. Although the exact cause of PD remains unknown, accumulating evidence suggests that brain infiltration of T cells plays a critical role in the pathogenesis of disease, contributing to neuroinflammation and dopaminergic neurodegeneration. Here, we used a mouse model of brain-infused aggregated αSYN, which recapitulates motor and non-motor dysfunctions seen in PD patients. We found that αSYN-induced motor dysfunction in mice is accompanied by an increased number of brain-residing Th17 (IL17+ CD4+) cells, but not CD8+ T cells. To evaluate whether the modulation of T cell response could rescue αSYN-induced damage, we chronically treated animals with abatacept (8 mg/kg, sc, 3x per week), a selective T-cell co-stimulation modulator. We found that abatacept treatment decreased Th1 (IFNƔ+ CD4+) and Th17 (IL17+ CD4+) cells in the brain, rescued motor function and prevented dopaminergic neuronal loss in αSYN-infused mice. These results highlight the significance of effector CD4+ T cells, especially Th17, in the progression of PD and introduce novel possibilities for repurposing immunomodulatory drugs used for arthritis as PD-modifying therapies.

Paleobiological implications of chevron pathology in the sauropodomorph Plateosaurus trossingensis from the Upper Triassic of SW Germany.

Paleopathology, the study of diseases and injuries from the fossil record, allows for a unique view into the life of prehistoric animals. Pathologies have nowadays been described in nearly all groups of fossil vertebrates, especially dinosaurs. Despite the large number of skeletons, pathologies had never been reported in the sauropodomorph Plateosaurus trossingensis. Here we describe the first pathologies of Plateosaurus using two individuals with pathologies in the chevrons of the tail, from the Upper Triassic of Trossingen, SW Germany. The two specimens each contain three consecutive pathological chevrons. Our results show that the pathologies were caused by external trauma in one individual and potentially tendinous trauma in the other. Healing of the lesions allowed survival of both animals. Using additional pathological specimens found in other collections and from multiple localities, we observe that 14.8% of all individuals of Plateosaurus contain pathologies within their chevrons, suggesting it was a vulnerable bone.

A juvenile pleurosaurid (Lepidosauria: Rhynchocephalia) from the Tithonian of the Mörnsheim Formation, Germany.

Late Jurassic rhynchocephalians from the Solnhofen Archipelago have been known for almost two centuries. The number of specimens and taxa is constantly increasing, but little is known about the ontogeny of these animals. The well-documented marine taxon Pleurosaurus is one of such cases. With over 15 described (and many more undescribed) specimens, there were no unambiguous juveniles so far. Some authors have argued that Acrosaurus, another common component of the Solnhofen Archipelago herpetofauna, might represent an early ontogenetic stage of Pleurosaurus, but the lack of proper descriptions for this taxon makes this assignment tentative, at best. Here, we describe the first unambiguous post-hatchling juvenile of Pleurosaurus and tentatively attribute it to Pleurosaurus cf. P. ginsburgi. The new specimen comes from the Lower Tithonian of the Mörnsheim Formation, Germany. This specimen is small, disarticulated, and incomplete, but preserves several of its craniomandibular bones and presacral vertebrae. It shares with Pleurosaurus a set of diagnostic features, such as an elongated and triangular skull, a low anterior flange in its dentition, and an elongated axial skeleton. It can be identified as a juvenile due to the presence of an unworn dentition, well-spaced posteriormost dentary teeth, a large gap between the last teeth and the coronoid process of the dentary, and poorly ossified vertebrae with unfused neural arches. Acrosaurus shares many anatomical features with both this specimen and Pleurosaurus, which could indicate that the two genera are indeed synonyms. The early ontogenetic stage inferred for the new Pleurosaurus specimen argues for an even earlier ontogenetic placement for specimens referred to Acrosaurus, the latter possibly pertaining to hatchlings.

Exercise and Protection from Age-Related Cognitive Decline.

In this chapter, we review the cross-sectional evidence in healthy human subjects for physical activity and cardiorespiratory fitness to offer neuroprotection and moderate cognitive decline in older age. The role of exercise training on cognition in healthy older adults and those diagnosed with mild cognitive impairment (MCI) is also discussed, including the evidence from neuroimaging studies that document changes to brain structure and function after a period of exercise training and improved fitness. Finally, in reference to animal models, the potential neurophysiological mechanisms for physical activity and exercise to impact human brain health are highlighted.

Cranial anatomy and phylogenetic affinities of Bolosaurus major, with new information on the unique bolosaurid feeding apparatus and evolution of the impedance-matching ear.

Resolving the phylogenetic relationships of early amniotes, in particular stem reptiles, remains a difficult problem. Three-dimensional morphological analysis of well-preserved stem-reptile specimens can reveal important anatomical data and clarify regions of phylogeny. Here, we present the first thorough description of the unusual early Permian stem reptile Bolosaurus major, including the first comprehensive description of a bolosaurid braincase. We describe previously obscured details of the palate, allowing for insight into bolosaurid feeding mechanics. Aspects of the rostrum, palate, mandible, and neurocranium suggest that B. major had a particularly strong bite. We additionally found B. major has a surprisingly slender stapes, similar to that of the middle Permian stem reptile Macroleter poezicus, which may suggest enhanced hearing abilities compared to other Paleozoic amniotes (e.g., captorhinids). We incorporated our new anatomical information into a large phylogenetic matrix (150 OTUs, 590 characters) to explore the relationship of Bolosauridae among stem reptiles. Our analyses generally recovered a paraphyletic "Parareptilia," and found Bolosauridae to diverge after Captorhinidae + Araeoscelidia. We also included B. major within a smaller matrix (10 OTUs, 27 characters) designed to explore the interrelationships of Bolosauridae and found all species of Bolosaurus to be monophyletic. While reptile relationships still require further investigation, our phylogeny suggests repeated evolution of impedance-matching ears in Paleozoic stem reptiles.

Xylem sap residue in cut-open conduits can affect gas discharge in pneumatic experiments.

Considerable attention has been paid to address methodological concerns related to measurements of embolism in conduits of angiosperm xylem. A fast, easy, and cheap method is based on gas extraction measurements from dehydrating samples to obtain pneumatic vulnerability curves (VCs). Here, we tested the assumption that cutting open conduits leads to gas-filled lumina when these are cut in air at fairly high water potentials, which is required to detect embolism in intact conduits. We performed VCs with the Pneumatron for 12 angiosperm species, and extracted sap from cut-open vessels in branches of nine species under early stages of branch dehydration. The optical method was applied to Citrus plants as an alternative reference method to estimate embolism resistance. We found an increase in gas discharge during early stages of dehydration, which affected the pneumatic VCs for most of the species studied. Xylem sap residue was not absorbed immediately by surrounding tissue in cut-open conduits in six of the nine species, but gradually disappeared over time during progressive dehydration. The amount of gas discharged increased until all residual sap was absorbed, and was not related to embolism. We conclude that residual xylem sap in cut-open conduits affects early stages of pneumatic VCs, and represents a novel artefact that can easily be corrected for. Yet, it remains unclear why exactly the air-water meniscus in cut-open conduits did not fully withdraw to the conduit end wall in most species. By analysing the slope of VCs over time, we could improve estimations of embolism resistance, as evidenced by a strong agreement between the pneumatic and the optical methods. Since residual sap in cut-open conduits of some species could slightly underestimate embolism resistance, we propose to apply a correction for this artefact based on the high time resolution measurements taken with a Pneumatron.

Monkey Bar-Associated Pediatric Fractures: A National Epidemiologic Study of Emergency Department Visits.

INTRODUCTION: Emergency department (ED) visits because of pediatric fractures are not only burdensome for patients and their families but also result in an increased healthcare expenditure. Almost half of all children experience at least one fracture by the age of 15. Many fractures occur in playgrounds, with monkey bars and other climbing apparatuses noted as frequent mechanisms of injury. Our purpose was to identify the pattern of injury and the population sustaining monkey bar-associated fractures. METHODS: We queried the National Electronic Injury Surveillance System database for all monkey bar-associated injuries in patients aged 0 to 18 years from January 1, 2009, to December 31, 2019. We described demographic data, patient disposition from the ED, fracture pattern, and injury setting using unweighted and weighted estimates. Weighted results that more closely reflect national estimates were calculated. RESULTS: During the study period, 30,920 (862,595 weighted) monkey bar-associated injuries presented to EDs; 16,410 (53.1%) (weighted injuries: 408,722 [47.4%]) were fracture injuries. The average age of kids sustaining fractures was 6.5 years, with most injuries (66.4%) occurring in kids between 6 and 12 years. A higher percentage of male patients presented to the ED with fractures compared with female patients (53% versus 47%). Upper extremity fractures were most common, 382,672 (94%) with forearm fractures constituting the majority (156,691 [38%]). Most children were treated and released (354,323 [87%]), with only 35,227 children (9%) being admitted for treatment. Places of recreation/sports were the most common setting of fractures (148,039 [36%]), followed by schools (159,784 [39%]). A notable association was observed between year and ethnicity and between month period and injury setting. CONCLUSION: Monkey bar-associated injuries are a major cause of upper extremity fractures in children, with most injuries occurring in recreational areas or schools. Young elementary school children are at the highest risk of injury. ED visits because of monkey bar-associated fractures have increased over the study period, and these injuries continue to be a major cause of fractures in children. Additional measures should be installed to decrease these preventable fractures among children, with schools as a potential starting point.

Unilateral hindlimb ischaemia-induced systemic inflammation is associated with non-ischaemic skeletal muscle inflammation.

Skeletal muscle atrophy and dysfunction commonly accompany cardiovascular diseases such as peripheral arterial disease and may be partially attributable to systemic inflammation. We sought to determine whether acute systemic inflammation in a model of hindlimb ischaemia (HLI) could affect skeletal muscle macrophage infiltration, fibre size, or capillarization, independent of the ischaemia. Eight-week-old C57BL/6 male mice underwent either Sham or HLI surgery, and were killed 1, 3, or 7 days post-surgery. Circulating inflammatory cytokine concentrations were measured, as well as immune cell infiltration and morphology of skeletal muscle from both limbs of HLI and Sham mice. In HLI compared with Sham mice at day 1, plasma interleukin-1ß levels were 216% higher (0.48 ± 0.10 vs. 0.15 ± 0.01 pg/µL, P = 0.005) and decreased by day 3. This was followed by increased macrophage presence in muscle from both ischaemic and non-ischaemic limbs of HLI mice by day 7 (7.3- and 2.3-fold greater than Sham, respectively, P < 0.0001). In HLI mice, muscle from the ischaemic limb had 21% lower fibre cross-sectional area than the non-ischaemic limb (724 ± 28 vs. 916 ± 46 µm2, P = 0.01), but the non-ischaemic limb of HLI mice was no different from Sham. This shows that HLI induces acute systemic inflammation accompanied by immune infiltration in both ischaemic and remote skeletal muscle; however, this did not induce skeletal muscle atrophy in remote muscle within the 7-day time course of this study. This effect of local skeletal muscle ischaemia on the inflammatory status of remote skeletal muscle may signal a priming of muscle for subsequent atrophy over a longer time course. HIGHLIGHTS: What is the central question of this study? Does hindlimb ischaemia-induced inflammation cause acute immune, inflammatory and morphological alterations in remote non-ischaemic skeletal muscle? What is the main finding and its importance? Hindlimb ischaemia induced systemic inflammation with subsequent neutrophil and macrophage infiltration in both ischaemic and non-ischaemic skeletal muscle; however, morphological changes did not occur in non-ischaemic muscle within 7 days. These immune alterations may have functional implications that take longer than 7 days to manifest, and subsequent or prolonged systemic inflammation and immune infiltration of muscle could lead to morphological changes and functional decline.

Real-World Treatment Patterns and Outcomes by Line of Therapy and Race in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Treated in the United States: Results From the Final Analysis of the Prospective, Observational, informCLL Registry.

BACKGROUND: informCLL is the largest US-based prospective, observational registry of patients with chronic lymphocytic leukemia (CLL) initiating FDA-approved treatment in the era of targeted therapy. PATIENTS AND METHODS: Patients were enrolled between October 2015 and June 2019. Data were collected for baseline characteristics, treatment patterns, outcomes, and safety. RESULTS: In total, 1459 eligible patients were enrolled (first line, n = 854; relapsed/refractory, n = 605). The most common index treatments were ibrutinib (first line, 45%; relapsed/refractory, 49%) and chemoimmunotherapy (first line, 43%; relapsed/refractory, 20%). With median follow-up of 31.8 and 30.9 months in first-line and relapsed/refractory cohorts, respectively, median time to next treatment (TTNT) in patients who received any index treatment was not reached (NR) and 48.6 months; estimated proportions without next-line therapy at 48 months were 64% and 50%. Median overall survival (OS) was NR for both cohorts; estimated 48-month OS rates were 81% and 64% in first-line and relapsed/refractory cohorts, respectively. In match-adjusted analyses, TTNT was improved with first-line ibrutinib versus chemoimmunotherapy (median NR vs. 56.5 months; hazard ratio, 0.74; 95% CI, 0.56-0.98). Exposure-adjusted rates of AEs leading to discontinuation and serious AEs were lower with ibrutinib versus chemoimmunotherapy. Estimated 36-month OS rates were similar in Black versus White patients who received any index treatment (first line, 87% vs. 83%; relapsed/refractory, 74% vs. 74%) or ibrutinib (first line, 97% vs. 85%; relapsed/refractory, 81% vs. 77%). CONCLUSION: In this prospective, large, real-world CLL registry, first-line ibrutinib was associated with longer TTNT than chemoimmunotherapy, with sustained benefit up to 4 years of follow-up.

The Role of Vitamin D in the Treatment of Carpal Tunnel Syndrome: Clinical and Electroneuromyographic Responses.

Carpal tunnel syndrome (CTS) is the most common cause of peripheral compressive neuropathy and consists of compression of the median nerve in the wrist. Although there are several etiologies, idiopathic is the most prevalent origin, and among the forms of treatment for CTS, conservative is the most indicated. However, despite the high prevalence in and impact of this syndrome on the healthcare system, there are still controversies regarding the best therapeutic approach for patients. Therefore, noting that some studies point to vitamin D deficiency as an independent risk factor, which increases the symptoms of the syndrome, this study evaluated the role of vitamin D supplementation and its influence on pain control, physical examination and response electroneuromyography to conservative treatment of carpal tunnel syndrome. For this, the sample consisted of 14 patients diagnosed with CTS and hypovitaminosis D, who were allocated into two groups. The control group received corticosteroid treatment, while the experimental group received corticosteroid treatment associated with vitamin D. Thus, from this study, it can be concluded that patients who received vitamin D, when compared to those who did not receive it, showed improvement in the degree of pain intensity, a reduction in symptom severity and an improvement in some electroneuromyographic parameters.

Validation of a Discharge Risk Calculator for Rural Patients Following Total Joint Arthroplasty.

BACKGROUND: As the volume of total joint arthroplasty in the US continues to grow, new challenges surrounding appropriate discharge surface. Arthroplasty literature has demonstrated discharge disposition to postacute care facilities carries major risks regarding the need for revision surgery, patient comorbidities, and financial burden. To quantify, categorize, and mitigate risks, a decision tool that uses preoperative patient variables has previously been published and validated using an urban patient population. The aim of our investigation was to validate the same predictive model using patients in a rural setting undergoing total knee arthroplasty (TKA) and total hip arthroplasty. METHODS: All TKA and THA procedures that were performed between January 2012 and September 2022 at our institution were collected. A total of 9,477 cases (39.6% TKA, 60.4% THA) were included for the validation analysis. There were 9 preoperative variables that were extracted in an automated fashion from the electronic medical record. Included patients were then run through the predictive model, generating a risk score representing that patient's differential risk of discharge to a skilled nursing facility versus home. Overall accuracy, sensitivity and specificity were calculated after obtaining risk scores. RESULTS: Score cutoff equally maximizing sensitivity and specificity was 0.23, and the proportion of correct classifications by the predictive tool in this study population was found to be 0.723, with an area under the curve of 0.788 - both higher than previously published accuracy levels. With the threshold of 0.23, sensitivity and specificity were found to be 0.720 and 0.723, respectively. CONCLUSIONS: The risk calculator showed very good accuracy, sensitivity, and specificity in predicting discharge location for rural patients undergoing TKA and THA, with accuracy even higher than in urban populations. The model provides an easy-to-use interface, with automation representing a viable tool in helping with shared decision-making regarding postoperative discharge plans.