Worsening of lymphopenia in patients with multiple sclerosis when switched from dimethyl fumarate to diroximel fumarate.

BACKGROUND: Diroximel fumarate (DRF) and dimethyl fumarate (DMF) are similar disease-modifying therapies (DMTs) that reduce disease activity in patients with relapsing-remitting multiple sclerosis (MS). We expect that patients on DRF would experience a similar incidence and severity of lymphopenia, given that it is a well-documented side effect of DMF treatment. METHODS: We utilized linear mixed-effects models to test for differences in white blood cell count (WBC), absolute lymphocyte count (ALC), absolute CD3+ count, absolute CD4+ count, and absolute CD8+ count over time in clinically stable patients with MS on DMF who switched to DRF. RESULTS: Twenty-two patients with MS who were clinically stable on DMF switched to DRF. Linear mixed-effects models showed a decrease in ALC when switching medications (ß = -225.70, p < 0.040). In addition, the models showed a decrease in absolute CD8+ counts after switches from DMF to DRF (ß = -85.59, p = 0.034). CONCLUSION: Patients with MS who are stable on DMF and switch to DRF may experience worsening of lymphopenia and lower absolute CD8+ counts, which may increase their risk of opportunistic infections. These findings indicate that close lymphocyte subset monitoring is clinically important when switching patients with MS from DMF to DRF.

Reassessment of pore occlusion in some diatom taxa with re-evaluation of Placoneis Mereschkowsky (Bacillariophyceae: Cymbellales) and description of two new genera.

In this article, the history and taxonomy of Placoneis gastrum, the type species of the genus Placoneis, was discussed. We investigated the structure of pore occlusions in Placoneis and related genera. As a result, we propose a new classification for tectulum-like types of pore occlusions. The new classification is congruent with previously-published and newly-constructed phylogenies based on molecular data. Based on the different structures of the pore occlusions, species of Placoneis are transferred to Witkowskia gen. nov. Hence, 168 new combinations are introduced. A new diatom species, with a similar morphology to Placoneis flabellata, was discovered in Bac Kan Province, Vietnam. It is described in this article as Chudaevia densistriata sp. nov. Placoneis flabellata is transferred to Chudaevia gen. nov. We also illustrate Placoneis flabellata herein and compare it to Chudaevia densistriata sp. nov. An unknown diatom, similar to Placoneis coloradensis, was discovered in Chukotka, Russia. It is introduced as Placoneis elinae sp. nov. below. Additionally, we discuss the distribution of some species of Witkowskia gen. nov. and Chudaevia gen. nov.

Increasing Body Mass Index Not Associated With Worse Patient-Reported Outcomes After Primary THA or TKA.

INTRODUCTION: As the US obesity epidemic continues to grow, so too does comorbid hip and knee arthritis. Strict body mass index (BMI) cutoffs for total hip and knee arthroplasty (THA and TKA) in the morbidly obese have been proposed and remain controversial, although current American Academy of Orthopaedic Surgeons guidelines recommend a BMI of less than 40 m/kg2 before surgery. This study sought to compare patient-reported outcomes and 30-day complication, readmission, and revision surgery rates after THA or TKA between morbidly obese patients and nonmorbidly obese control subjects. METHODS: All patients undergoing primary THA and TKA at our institution from May 2020 to July 2022 were identified. Patient demographics, surgical time, length of stay and 30-day readmission, revision surgery, and complication rates were prospectively collected. Preoperative and postoperative Hip and Knee Society (Hip Osteoarthritis Outcome Score [HOOS] and Knee Osteoarthritis Outcome Score [KOOS]) were collected. Patients were stratified by BMI as ideal weight (20 to 24.9), overweight (25 to 29.9), class I obese (30 to 34.9), class II obese (35 to 39.9), and morbidly obese (>40 m/kg2). RESULTS: A total of 1,423 patients were included for final analysis. No difference was observed in 30-day unplanned return to emergency department, readmission, or revision surgery in the morbidly obese cohort. Morbidly obese patients undergoing THA had lower preoperative HOOS (49.5 versus 54.5, P = 0.004); however, there was no difference in postoperative HOOS or KOOS at 12 months across all cohorts. DISCUSSION: No difference was observed in 30-day return to emergency department, readmission, or revision surgery in the morbidly obese cohort. Despite a lower preoperative HOOS, there was no difference in 12-month HOOS or KOOS when stratified by BMI. These findings suggest that such patients may achieve similar benefit from arthroplasty as their ideal weight counterparts.

HIV-Associated Neurocognitive Disorder: A Look into Cellular and Molecular Pathology.

Despite combined antiretroviral therapy (cART) limiting HIV replication to undetectable levels in the blood, people living with HIV continue to experience HIV-associated neurocognitive disorder (HAND). HAND is associated with neurocognitive impairment, including motor impairment, and memory loss. HIV has been detected in the brain within 8 days of estimated exposure and the mechanisms for this early entry are being actively studied. Once having entered into the central nervous system (CNS), HIV degrades the blood-brain barrier through the production of its gp120 and Tat proteins. These proteins are directly toxic to endothelial cells and neurons, and propagate inflammatory cytokines by the activation of immune cells and dysregulation of tight junction proteins. The BBB breakdown is associated with the progression of neurocognitive disease. One of the main hurdles for treatment for HAND is the latent pool of cells, which are insensitive to cART and prolong inflammation by harboring the provirus in long-lived cells that can reactivate, causing damage. Multiple strategies are being studied to combat the latent pool and HAND; however, clinically, these approaches have been insufficient and require further revisions. The goal of this paper is to aggregate the known mechanisms and challenges associated with HAND.

Joint EANM-SNMMI guideline on the role of 2-[18F]FDG PET/CT in no special type breast cancer : (endorsed by the ACR, ESSO, ESTRO, EUSOBI/ESR, and EUSOMA).

INTRODUCTION: There is much literature about the role of 2-[18F]FDG PET/CT in patients with breast cancer (BC). However, there exists no international guideline with involvement of the nuclear medicine societies about this subject. PURPOSE: To provide an organized, international, state-of-the-art, and multidisciplinary guideline, led by experts of two nuclear medicine societies (EANM and SNMMI) and representation of important societies in the field of BC (ACR, ESSO, ESTRO, EUSOBI/ESR, and EUSOMA). METHODS: Literature review and expert discussion were performed with the aim of collecting updated information regarding the role of 2-[18F]FDG PET/CT in patients with no special type (NST) BC and summarizing its indications according to scientific evidence. Recommendations were scored according to the National Institute for Health and Care Excellence (NICE) criteria. RESULTS: Quantitative PET features (SUV, MTV, TLG) are valuable prognostic parameters. In baseline staging, 2-[18F]FDG PET/CT plays a role from stage IIB through stage IV. When assessing response to therapy, 2-[18F]FDG PET/CT should be performed on certified scanners, and reported either according to PERCIST, EORTC PET, or EANM immunotherapy response criteria, as appropriate. 2-[18F]FDG PET/CT may be useful to assess early metabolic response, particularly in non-metastatic triple-negative and HER2+ tumours. 2-[18F]FDG PET/CT is useful to detect the site and extent of recurrence when conventional imaging methods are equivocal and when there is clinical and/or laboratorial suspicion of relapse. Recent developments are promising. CONCLUSION: 2-[18F]FDG PET/CT is extremely useful in BC management, as supported by extensive evidence of its utility compared to other imaging modalities in several clinical scenarios.

Cocconeiscrisscrossis sp. nov., a new monoraphid diatom (Bacillariophyta) from southern China.

A novel monoraphid diatom species, Cocconeiscrisscrossis You, Yu, Kociolek & Wang, sp. nov. is examined and described from the Qingyi River and Maolan Nature Reserve of southern China. The morphological description is based on light microscopy and scanning electron microscopy observations and the new species is compared with similar taxa in this genus. The characteristics unique to Cocconeiscrisscrossissp. nov. include its central area extending irregularly to both sides, it having closed valvocopulae with heavily silicified fimbriate margins and poles of the valvocopulae have 'sword-shaped' siliceous extensions. These features differentiate this new species from others in the genus. This new species was found in alkaline waterbodies, including streams, waterfall and ponds. It was usually found as an epiphyte on the stones; however, it was present on other substrates such as mosses.

A method for assessing student ability to apply anatomical knowledge within a traditional anatomy laboratory examination.

Fidelity between teaching activities and assessment methods is an important goal of knowledge and performance evaluations in medical education. Ideally, assessment methods provide evidence of learning that reflects the types of knowledge described in the learning objectives of the course. The most reliable assessments involve the same or similar tasks as those used during the instructional components of the course. Our preclinical human anatomy course includes, in addition to traditional lecture and cadaver-based laboratory learning activities, a series of applied human anatomy learning activities intended to emphasize human anatomy as it is encountered in living human individuals. The learning activities involve psychomotor behaviors including inspection, palpation, and auscultation, techniques used in the physical examination, as well as other activities designed to emphasize anatomical structures and tissues as they may be found in patient populations. We describe here our method for measuring student success in learning human anatomy in this manner, highlighting the direct linkage between the learning activities and the assessment tasks. We describe our performance scoring method and how we include this data in the calculation of an anatomy examination grade. As an indicator of our success with this approach, we include performance scores for the applied anatomy questions included on the laboratory component of our unit examinations for two successive academic years. We conclude with summary comments from students regarding the applied anatomy learning activities and assessment approach and offer suggestions for addressing specific challenges associated with the use of these types of assessment methods.

Acute post-orchiectomy pain does not reduce alpha rams' interest in feed resources.

Sheep pain is an animal welfare issue monitored based on behavioral responses, including appetite. Dominant (alpha) males have priority for accessing limited feed resources, however, the effects of pain on feed interest in members of a group with defined social hierarchy are unknown. Our objective was to investigate effects of acute post-orchiectomy pain on alpha rams' interest in accessing a limited feed resource. Eighteen rams were randomly housed in pens of 3 rams. After acclimation, the first 5-d (consecutive) battery of a behavior test was performed. In this test, 180 g of the regular diet concentrate was placed in a portable trough in the center of the pen; this feed was supplemental to the diet and represented a limited, albeit strongly preferable feed resource. Rams were filmed for 5 min after the feed introduction. Hierarchical levels (alpha, beta, and gamma) were defined based on the social hierarchical index according to higher initiator and lower receptor agonistic behaviors from the social network analyses. After 15 d, a second 5-d behavioral test battery was repeated. On the following day, alpha rams were castrated. Flunixin meglumine was given immediately before surgery and a final behavioral test was performed 8 h post-orchiectomy, concurrent with an expected peak in postoperative pain. For all recordings, the latency, frequency, and duration of time that each ram had its mouth inside the feed trough were recorded, and the Unesp-Botucatu sheep acute pain scale pain scale (USAPS) was applied. The social hierarchical index was highest in alpha rams, followed by beta and gamma. The pain scores were statistically equivalent across the 11 evaluation days for beta and gamma rams, whereas there was an increase in the final evaluation for alpha. There was no difference in latency, frequency, and duration between alpha, beta, and gamma rams across evaluations. We concluded that acute post-orchiectomy pain did not decrease alpha rams' interest in accessing limited feed. Routine feeding offers a valuable chance to detect pain-related behavior using the USAPS in rams. However, dominance may confound appetite-related behaviors in assessing acute pain, as alpha rams' interest in limited feed remained unaffected by the pain.

Simplifying stable CHO cell line generation with high probability of monoclonality by using microfluidic dispensing as an alternative to fluorescence activated cell sorting.

Single cell cloning is a critical step for cell line development (CLD) for therapeutic protein production, with proof of monoclonality being compulsorily sought in regulatory filings. Among the different single cell deposition technologies, we found that fluorescence activated cell sorting (FACS) offers high probability of monoclonality and can allow selective enrichment of the producer cells. However, FACS instruments are expensive and resource-intensive, have a large footprint, require highly skilled operators and take hours for setup, thereby complicating the cell line generation process. With the aim of finding an easy-to-use alternative to FACS, we identified a flow cytometry-based microfluidic cell dispenser, which presents a single cell sorting solution for biopharmaceutical CLD. The microfluidic cell dispenser is small, budget-friendly, easy-to-use, requires lower-cost consumables, permits flow cytometry-enabled multiparametric target cell enrichment and offers fast and gentle single cell dispensing into multiwell plates. Following comprehensive evaluation, we found that single cell deposition by the microfluidic cell dispenser resulted in >99% probability of monoclonality for production cell lines. Moreover, the clonally derived producer cell lines generated from the microfluidic cell dispenser demonstrated comparable or improved growth profiles and production capability compared to the FACS derived cell lines. Taken together, microfluidic cell dispensing can serve as a cost-effective, efficient and convenient alternative to FACS, simplifying the biopharmaceutical CLD platform with significant reductions in both scientist time and running costs.

Almanac - Retrieval-Augmented Language Models for Clinical Medicine.

BACKGROUND: Large language models (LLMs) have recently shown impressive zero-shot capabilities, whereby they can use auxiliary data, without the availability of task-specific training examples, to complete a variety of natural language tasks, such as summarization, dialogue generation, and question answering. However, despite many promising applications of LLMs in clinical medicine, adoption of these models has been limited by their tendency to generate incorrect and sometimes even harmful statements. METHODS: We tasked a panel of eight board-certified clinicians and two health care practitioners with evaluating Almanac, an LLM framework augmented with retrieval capabilities from curated medical resources for medical guideline and treatment recommendations. The panel compared responses from Almanac and standard LLMs (ChatGPT-4, Bing, and Bard) versus a novel data set of 314 clinical questions spanning nine medical specialties. RESULTS: Almanac showed a significant improvement in performance compared with the standard LLMs across axes of factuality, completeness, user preference, and adversarial safety. CONCLUSIONS: Our results show the potential for LLMs with access to domain-specific corpora to be effective in clinical decision-making. The findings also underscore the importance of carefully testing LLMs before deployment to mitigate their shortcomings. (Funded by the National Institutes of Health, National Heart, Lung, and Blood Institute.).

Promotion in Place: A Model for Competency-Based, Time-Variable Graduate Medical Education.

PROBLEM: Competency-based medical education is increasingly regarded as a preferred framework for physician training, but implementation is limited. U.S. residency programs remain largely time based, with variable assessments and limited opportunities for individualization. Gaps in graduates' readiness for unsupervised care have been noted across specialties. Logistical barriers and regulatory requirements constrain movement toward competency-based, time-variable (CBTV) graduate medical education (GME), despite its theoretical benefits. APPROACH: The authors describe a vision for CBTV-GME and an implementation model that can be applied across specialties. Termed "Promotion in Place" (PIP), the model relies on enhanced assessment, clear criteria for advancement, and flexibility to adjust individuals' responsibilities and time in training based on demonstrated competence. PIP allows a resident's graduation to be advanced or delayed accordingly. Residents deemed competent for early graduation can transition to attending physician status within their training institution and benefit from a period of "sheltered independence" until the standard graduation date. Residents who need extended time to achieve competency have graduation delayed to incorporate additional targeted education. OUTCOMES: A proposal to pilot the PIP model of CBTV-GME received funding through the American Medical Association's "Reimagining Residency" initiative in 2019. Ten of 46 residency programs in a multihospital system expressed interest and pursued initial planning. Seven programs withdrew for reasons including program director transitions, uncertainty about resident reactions, and the COVID-19 pandemic. Three programs petitioned their specialty boards for exemptions from time-based training. One program was granted the needed exemption and launched a PIP pilot, now in year 4, demonstrating the feasibility of implementing this model. Implementation tools and templates are described. NEXT STEPS: Larger-scale implementation with longer-term assessment is needed to evaluate the impact and generalizability of this CBTV-GME model.

A new species of genus Crenotia (Bacillariophyta) from Tibet, China.

During the investigation of the freshwater diatoms from Tibet, a monoraphid species was observed from a hot spring near Anduo County, located on a plateau in the central portion of Tibet. This species shares the diagnostic features of Crenotia, such as the valve bent along the transapical axis, striae uniseriate to biseriate from centre to the apices and areolae with special structures located at the end of each stria. We compared the morphological characters of this new species with the others in this genus and show it to be new; it is named Crenotiatibetiasp. nov. This species has small valves with slightly protracted ends with nearly capitate apices, lanceolate axial area, central area unilaterally expanded to the margin, striae uniseriate to biseriate, but, in some valves, the striae are only uniseriate. Areolae are round small to irregular in shape and, at the end of each stria, there is a horseshoe-shaped areola present. Observations of developing valves show all the striae begin biseriate, then they become covered by silica to form uniseriate striae. Comparisons are made amongst the species in this genus and with genera assigned to the Achnanthidiaceae.