Harnessing cellular therapeutics for type 1 diabetes mellitus: progress, challenges, and the road ahead.

Type 1 diabetes mellitus (T1DM) is a growing global health concern that affects approximately 8.5 million individuals worldwide. T1DM is characterized by an autoimmune destruction of pancreatic ß cells, leading to a disruption in glucose homeostasis. Therapeutic intervention for T1DM requires a complex regimen of glycaemic monitoring and the administration of exogenous insulin to regulate blood glucose levels. Advances in continuous glucose monitoring and algorithm-driven insulin delivery devices have improved the quality of life of patients. Despite this, mimicking islet function and complex physiological feedback remains challenging. Pancreatic islet transplantation represents a potential functional cure for T1DM but is hindered by donor scarcity, variability in harvested cells, aggressive immunosuppressive regimens and suboptimal clinical outcomes. Current research is directed towards generating alternative cell sources, improving transplantation methods, and enhancing cell survival without chronic immunosuppression. This Review maps the progress in cell replacement therapies for T1DM and outlines the remaining challenges and future directions. We explore the state-of-the-art strategies for generating replenishable ß cells, cell delivery technologies and local targeted immune modulation. Finally, we highlight relevant animal models and the regulatory aspects for advancing these technologies towards clinical deployment.

Impact of high rheumatoid factor levels on treatment outcomes with certolizumab pegol and adalimumab in patients with rheumatoid arthritis.

OBJECTIVE: To assess the impact of baseline rheumatoid factor (RF) level on drug concentrations and efficacy of certolizumab pegol (CZP; tumour necrosis factor inhibitor [TNFi] without a crystallisable fragment [Fc]) and adalimumab (ADA; Fc-containing TNFi) in patients with rheumatoid arthritis (RA). METHODS: The phase 4 EXXELERATE study (NCT01500278) was a 104-week, randomised, single-blind (double-blind until week 12; investigator-blind thereafter), head-to-head study of CZP vs ADA in patients with RA. In this post hoc analysis, we report drug concentration and efficacy outcomes stratified by baseline RF quartile (≤Q3 or >Q3). RESULTS: Baseline data by RF quartiles were available for 453 CZP-randomised and 454 ADA-randomised patients (≤Q3: ≤204 IU/ml; >Q3: >204 IU/ml). From week 12, the area under the curve (AUC) of ADA concentration was lower in patients with RF > 204 IU/ml vs patients with RF ≤ 204 IU/ml; the AUC of CZP concentration was similar in patients with RF ≤ 204 IU/ml and >204 IU/ml. For patients with RF ≤ 204 IU/ml, disease activity score (DAS28)-C-reactive protein (CRP) was similar between CZP- and ADA-treated patients through week 104. For patients with RF > 204 IU/ml, mean DAS28-CRP was lower in CZP- vs ADA-treated patients at week 104. The proportion of patients with RF > 204 IU/ml achieving DAS28-CRP low disease activity at week 104 was greater in CZP- vs ADA-treated patients. CONCLUSION: CZP was associated with maintained drug concentration and efficacy in patients with RA and high RF and may therefore be a more suitable therapeutic option than TNFis with an Fc fragment in these patients.

In sepsis or septic shock, prolonged vs. intermittent infusion of ß-lactam antibiotics reduces mortality at 90 d.

SOURCE CITATION: Abdul-Aziz MH, Hammond NE, Brett SJ, et al. Prolonged vs intermittent infusions of ß-lactam antibiotics in adults with sepsis or septic shock: a systematic review and meta-analysis. JAMA. 12 June 2024. [Epub ahead of print.] 38864162.

In sepsis, continuous and intermittent infusion of ß-lactam antibiotics did not differ for mortality at 90 d.

SOURCE CITATION: Dulhunty JM, Brett SJ, De Waele JJ, et al; BLING III Study Investigators. Continuous vs intermittent ß-lactam antibiotic infusions in critically ill patients with sepsis: the BLING III randomized clinical trial. JAMA. 12 June 2024. [Epub ahead of print.] 38864155.

Cognitive Control Moderates Associations Between Domains of Temperamental Reactivity and Preschoolers' Social Behaviors.

Temperamental characteristics and emerging cognitive control are meaningful predictors of children's development of adaptive and maladaptive social behaviors during the preschool period. However, knowledge of the interplay of these pathways, when examined concurrently to highlight their individual contributions, is limited. Using a cross-sectional sample of 3-year-old children, we examined parent-reported discrete traits of negative (anger, fear, sadness, and shyness) and positive (low- and high-intensity pleasure) temperamental reactivity as predictors of children's prosociality and physical aggression. Further, we tested whether the effects of discrete temperament were moderated by cognitive control, as indexed by the N2 event-related potential, during a go/no-go task. Analyses focus on a subsample of children with an observable N2 (n = 66). When controlling for other relative temperament traits, several significant main effects emerged. Moreover, at low cognitive control (smaller N2), fear was negatively associated with aggression, whereas at high cognitive control, sadness was positively associated with aggression. Heightened anger was linked to reduced prosocial behavior when cognitive control was low but linked to greater prosocial behavior when cognitive control was high. The results highlight that discrete temperament traits predict individual differences in child outcomes but that associations depend on concurrent levels of cognitive control.

Analysis of ductal carcinoma in situ by self-reported race reveals molecular differences related to outcome.

BACKGROUND: Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive breast cancer (IBC). Studies have indicated differences in DCIS outcome based on race or ethnicity, but molecular differences have not been investigated. METHODS: We examined the molecular profile of DCIS by self-reported race (SRR) and outcome groups in Black (n = 99) and White (n = 191) women in a large DCIS case-control cohort study with longitudinal follow up. RESULTS: Gene expression and pathway analyses suggested that different genes and pathways are involved in diagnosis and ipsilateral breast outcome (DCIS or IBC) after DCIS treatment in White versus Black women. We identified differences in ER and HER2 expression, tumor microenvironment composition, and copy number variations by SRR and outcome groups. CONCLUSIONS: Our results suggest that different molecular mechanisms drive initiation and subsequent ipsilateral breast events in Black versus White women.

What we mean when we say semantic: Toward a multidisciplinary semantic glossary.

Tulving characterized semantic memory as a vast repository of meaning that underlies language and many other cognitive processes. This perspective on lexical and conceptual knowledge galvanized a new era of research undertaken by numerous fields, each with their own idiosyncratic methods and terminology. For example, "concept" has different meanings in philosophy, linguistics, and psychology. As such, many fundamental constructs used to delineate semantic theories remain underspecified and/or opaque. Weak construct specificity is among the leading causes of the replication crisis now facing psychology and related fields. Term ambiguity hinders cross-disciplinary communication, falsifiability, and incremental theory-building. Numerous cognitive subdisciplines (e.g., vision, affective neuroscience) have recently addressed these limitations via the development of consensus-based guidelines and definitions. The project to follow represents our effort to produce a multidisciplinary semantic glossary consisting of succinct definitions, background, principled dissenting views, ratings of agreement, and subjective confidence for 17 target constructs (e.g., abstractness, abstraction, concreteness, concept, embodied cognition, event semantics, lexical-semantic, modality, representation, semantic control, semantic feature, simulation, semantic distance, semantic dimension). We discuss potential benefits and pitfalls (e.g., implicit bias, prescriptiveness) of these efforts to specify a common nomenclature that other researchers might index in specifying their own theoretical perspectives (e.g., They said X, but I mean Y).

CDK5-cyclin B1 regulates mitotic fidelity.

CDK1 has been known to be the sole cyclin-dependent kinase (CDK) partner of cyclin B1 to drive mitotic progression1. Here we demonstrate that CDK5 is active during mitosis and is necessary for maintaining mitotic fidelity. CDK5 is an atypical CDK owing to its high expression in post-mitotic neurons and activation by non-cyclin proteins p35 and p392. Here, using independent chemical genetic approaches, we specifically abrogated CDK5 activity during mitosis, and observed mitotic defects, nuclear atypia and substantial alterations in the mitotic phosphoproteome. Notably, cyclin B1 is a mitotic co-factor of CDK5. Computational modelling, comparison with experimentally derived structures of CDK-cyclin complexes and validation with mutational analysis indicate that CDK5-cyclin B1 can form a functional complex. Disruption of the CDK5-cyclin B1 complex phenocopies CDK5 abrogation in mitosis. Together, our results demonstrate that cyclin B1 partners with both CDK5 and CDK1, and CDK5-cyclin B1 functions as a canonical CDK-cyclin complex to ensure mitotic fidelity.

Two new species of Dulcicalothrix (Nostocales, Cyanobacteria) from India and erection of Brunnivagina gen. nov., with observations on the problem of using multiple ribosomal operons in cyanobacterial taxonomy.

Two new species of Dulcicalothrix, D. adhikaryi sp. nov. and D. iyengarii sp. nov., were discovered in India and are characterized and described in accordance with the rules of the International Code of Nomenclature for algae, fungi, and plants (ICN). As a result of phylogenetic analysis, Calothrix elsteri is reassigned to Brunnivagina gen. nov. During comparison with all Dulcicalothrix for which sequence data were available, we observed that the genus has six ribosomal operons in three orthologous types. Each of the three orthologs could be identified based upon indels occurring in the D1-D1' helix sequence in the ITS rRNA region between the 16S and 23S rRNA genes, and in these three types, there were operons containing ITS rRNA regions with and without tRNA genes. Examination of complete genomes in Dulcicalothrix revealed that, at least in the three strains for which complete genomes are available, there are five ribosomal operons, two with tRNA genes and three with no tRNA genes in the ITS rRNA region. Internal transcribed spacer rRNA regions have been consistently used to differentiate species, both on the basis of secondary structure and percent dissimilarity. Our findings call into question the use of ITS rRNA regions to differentiate species in the absence of efforts to obtain multiple operons of the ITS rRNA region through cloning or targeted PCR amplicons. The ITS rRNA region data for Dulcicalothrix is woefully incomplete, but we provide herein a means for dealing with incomplete data using the polyphasic approach to analyze diverse molecular character sets. Caution is urged in using ITS rRNA data, but a way forward through the complexity is also proposed.

Do bats' social vocalizations conform to Zipf's law and the Menzerath-Altmann law?

The study of vocal communication in non-human animals can uncover the roots of human languages. Recent studies of language have focused on two linguistic laws: Zipf's law and the Menzerath-Altmann law. However, whether bats' social vocalizations follow these linguistic laws, especially Menzerath's law, has largely been unexplored. Here, we used Asian particolored bats, Vespertilio sinensis, to examine whether aggressive vocalizations conform to Zipf's and Menzerath's laws. Aggressive vocalizations of V. sinensis adhere to Zipf's law, with the most frequent syllables being the shortest in duration. There was a negative association between the syllable number within a call and the average syllable duration, in agreement with Menzerath's law. A decrease in the proportion of some long syllables and a decrease in the duration of several syllable types in long-duration calls explain the occurrence of this law. Our results indicate that a general compression principle organizes aspects of bat vocal communication systems.

Relations Among Multiple Dimensions of Self-Reported Listening Effort in Response to an Auditory Psychomotor Vigilance Task.

PURPOSE: Listening effort is a broad construct, and there is no consensus on how to subdivide listening effort into dimensions. This project focuses on the subjective experience of effortful listening and tests if cognitive workload, mental fatigue, and mood are interrelated dimensions. METHOD: Two online studies tested young adults (n = 74 and n = 195) and measured subjective workload, fatigue (subscales of fatigue and energy), and mood (subscales of positive and negative mood) before and after a challenging listening task. In the listening effort task, participants responded to intermittent 1-kHz target tones in continuous white noise for approximately 12 min. RESULTS: Correlations and principal component analysis showed that fatigue and mood were distinct but interrelated constructs that weakly correlated with workload. Effortful listening provoked increased fatigue and decreased energy and positive mood yet did not influence negative mood or workload. CONCLUSIONS: The findings suggest that self-reported listening effort has multiple dimensions that can have different responses to the same effortful listening episode. The results can help guide evidence-based development of clinical listening effort tests and may reveal mechanisms for how listening effort relates to quality of life in those with hearing impairment. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.26418976.

Introducing prediction intervals for sample means.

Researchers and practitioners are typically familiar with descriptive statistics and statistical inference. However, outside of regression techniques, little attention may be given to questions around prediction. In the current paper, we introduce prediction intervals using fundamental concepts that are learned in descriptive and inferential statistical training (i.e., sampling error, standard deviation). We walk through an example using simple hand calculations and reference a simple R package that can be used to calculate prediction intervals.

Geometric Tuning of Coordinatively Unsaturated Copper(I) Sites in Metal-Organic Frameworks for Ambient-Temperature Hydrogen Storage.

Porous solids can accommodate and release molecular hydrogen readily, making them attractive for minimizing the energy requirements for hydrogen storage relative to physical storage systems. However, H2 adsorption enthalpies in such materials are generally weak (-3 to -7 kJ/mol), lowering capacities at ambient temperature. Metal-organic frameworks with well-defined structures and synthetic modularity could allow for tuning adsorbent-H2 interactions for ambient-temperature storage. Recently, Cu2.2Zn2.8Cl1.8(btdd)3 (H2btdd = bis(1H-1,2,3-triazolo-[4,5-b],[4',5'-i])dibenzo[1,4]dioxin; CuI-MFU-4l) was reported to show a large H2 adsorption enthalpy of -32 kJ/mol owing to π-backbonding from CuI to H2, exceeding the optimal binding strength for ambient-temperature storage (-15 to -25 kJ/mol). Toward realizing optimal H2 binding, we sought to modulate the π-backbonding interactions by tuning the pyramidal geometry of the trigonal CuI sites. A series of isostructural frameworks, Cu2.7M2.3X1.3(btdd)3 (M = Mn, Cd; X = Cl, I; CuIM-MFU-4l), was synthesized through postsynthetic modification of the corresponding materials M5X4(btdd)3 (M = Mn, Cd; X = CH3CO2, I). This strategy adjusts the H2 adsorption enthalpy at the CuI sites according to the ionic radius of the central metal ion of the pentanuclear cluster node, leading to -33 kJ/mol for M = ZnII (0.74 Å), -27 kJ/mol for M = MnII (0.83 Å), and -23 kJ/mol for M = CdII (0.95 Å). Thus, CuICd-MFU-4l provides a second, more stable example of optimal H2 binding energy for ambient-temperature storage among reported metal-organic frameworks. Structural, computational, and spectroscopic studies indicate that a larger central metal planarizes trigonal CuI sites, weakening the π-backbonding to H2.

Diffusion Tensor Imaging in Boys With Adrenoleukodystrophy: Identification of Cerebral Disease and Association With Neurocognitive Outcomes.

BACKGROUND AND OBJECTIVES: Childhood cerebral adrenoleukodystrophy (C-ALD) is a severe inflammatory demyelinating disease that must be treated at an early stage to prevent permanent brain injury and neurocognitive decline. In standard clinical practice, C-ALD lesions are detected and characterized by a neuroradiologist reviewing anatomical MRI scans. We aimed to assess whether diffusion tensor imaging (DTI) is sensitive to the presence and severity of C-ALD lesions and to investigate associations with neurocognitive outcomes after hematopoietic cell therapy (HCT). METHODS: In this retrospective cohort study, we analyzed high-resolution anatomical MRI, DTI, and neurocognitive assessments from boys with C-ALD undergoing HCT at the University of Minnesota between 2011 and 2021. Longitudinal DTI data were compared with an age-matched group of boys with ALD and no lesion (NL-ALD). DTI metrics were obtained for atlas-based regions of interest (ROIs) within 3 subdivisions of the corpus callosum (CC), corticospinal tract (CST), and total white matter (WM). Between-group baseline and slope differences in fractional anisotropy (FA) and axial (AD), radial (RD), and mean (MD) diffusivities were compared using analysis of covariance accounting for age, MRI severity (Loes score), and lesion location. RESULTS: Among patients with NL-ALD (n = 14), stable or increasing FA, stable AD, and stable or decreasing RD and MD were generally observed during the 1-year study period across all ROIs. In comparison, patients with mild posterior lesions (Loes 1-2; n = 13) demonstrated lower baseline FA in the CC splenium (C-ALD 0.50 ± 0.08 vs NL-ALD 0.58 ± 0.04; pBH = 0.022 adjusted Benjamini-Hochberg p-value), lower baseline AD across ROIs (e.g., C-ALD 1.34 ± 0.03 ×10-9 m2/s in total WM vs NL-ALD 1.38 ± 0.04 ×10-9 m2/s; pBH = 0.005), lower baseline RD in CC body and CST, and lower baseline MD across ROIs except CC splenium. Longitudinal slopes in CC splenium showed high sensitivity and specificity in differentiating early C-ALD from NL-ALD. Among all patients with C-ALD (n = 38), baseline Loes scores and DTI metrics were associated with post-HCT neurocognitive functions, including processing speed (e.g., FA WM Spearman correlation coefficient R = 0.64) and visual-motor integration (e.g., FA WM R = 0.71). DISCUSSION: DTI was sensitive to lesion presence and severity as well as clinical neurocognitive effects of C-ALD. DTI metrics quantify C-ALD even at an early stage.

Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies.

Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer's disease (AD), with recent proteomic studies highlighting disrupted glial metabolism in AD. We report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN), rescues hippocampal memory function in mouse preclinical models of AD by restoring astrocyte metabolism. Activation of astrocytic IDO1 by amyloid ß and tau oligomers increases KYN and suppresses glycolysis in an aryl hydrocarbon receptor-dependent manner. In amyloid and tau models, IDO1 inhibition improves hippocampal glucose metabolism and rescues hippocampal long-term potentiation in a monocarboxylate transporter-dependent manner. In astrocytic and neuronal cocultures from AD subjects, IDO1 inhibition improved astrocytic production of lactate and uptake by neurons. Thus, IDO1 inhibitors presently developed for cancer might be repurposed for treatment of AD.

Implementing a Metabolism-informed approach for smoking cessation in an Alaska Tribal health system: study protocol for a single-arm implementation pilot trial.

BACKGROUND: Individualized treatment for commercial tobacco smoking cessation, such as through the utilization of the nicotine metabolite ratio (NMR), offers potential clinical benefit. NMR is a metabolism-informed biomarker that can be used to guide medication selection. NMR testing is particularly promising for tobacco cessation efforts in populations with high rates of smoking, such as some Alaska Native and American Indian (AN/AI) communities. To date, no prior study has evaluated the implementation of NMR-guided tobacco cessation with AN/AI populations. METHODS: The present "QUIT" protocol is a two-phase study that will occur at Southcentral Foundation (SCF), an Alaska Native-owned health system, serving 70,000 AN/AI people, based in Anchorage, Alaska. In Phase one, qualitative interviews with customer-owners (patients), providers and administrators (n = 36) and a 10-participant beta-test will be used to refine a strategy to implement NMR testing in the health system. Phase two will involve a single-arm pilot trial (n = 50) and qualitative interviews throughout data collection (n = 48) to evaluate the implementation strategy and explore the real-world acceptability and feasibility of NMR testing to guide tobacco cessation with AN/AI populations. DISCUSSION: This study utilizes a community-based participatory approach to refine and implement a nicotine metabolism-informed smoking cessation program in a Tribal healthcare setting. The process and findings from this study will reflect the importance of customer-owner choice and honor the lived experience involved in quitting commercial tobacco. Pilot study data will inform the effect and sample sizes required for a future pragmatic trial of NMR-guided smoking cessation. TRIAL REGISTRATION: This study will be registered with clinicaltrials.gov after the beta test is complete and the final IRB protocol is approved.

The Relationship Between All-Suture and Solid Medial-Row Anchors and Patient-Reported Outcomes for Double-Row Suture Bridge Rotator Cuff Repair.

Background: The use of all-suture anchors for rotator cuff repair is increasing. Potential benefits include decreased bone loss and decreased damage to the chondral surface. Minimal evidence exists comparing outcomes among medial-row anchor fixation methods in double-row suture bridge rotator cuff repair. Purpose: To compare the clinical outcomes between all-suture and solid medial-row anchors in double-row suture bridge rotator cuff repair. Study Design: Case series; Level of evidence, 4. Methods: A total of 352 patients (mean age at surgery, 60.3 years) underwent double-row suture bridge rotator cuff repair at our institution. Patients were separated into 2 groups based on whether they underwent all-suture (n = 280) or solid (n = 72) anchor fixation for the medial row. Outcomes data were collected via an ongoing longitudinal data repository or through telephone calls (minimum follow-up time, 2.0 years; mean follow-up time, 3.0 years). Outcomes were evaluated using the American Shoulder and Elbow Surgeons (ASES) standardized shoulder assessment form and the visual analog scale (VAS). The same rehabilitation protocol was administered to all patients. The proportions of patients meeting previously published Patient Acceptable Symptom State (PASS) thresholds were calculated for the outcome measures, and outcome scores and the proportions of patients meeting PASS thresholds between groups were compared using linear and logistic regression, respectively. Results: The groups did not differ in terms of age at surgery, sex distribution, rotator cuff tear size, or number of medial-row anchors used. The solid anchor group had a longer follow-up time compared with the all-suture anchor group (3.6 ± 0.7 vs 2.8 ± 0.8 years, respectively; P < .01). After controlling for follow-up time, the solid and all-suture anchor groups did not differ in ASES scores (89.6 ± 17.8 vs 88.8 ± 16.7, respectively; P = .44) or VAS scores (1.1 ± 2.1 vs 1.2 ± 2.1, respectively; P = .37). Similarly, after controlling for follow-up time, the solid and all-suture anchor groups did not differ in the proportions of patients meeting PASS cutoffs for the ASES (84.7% vs 80.7%, respectively; P = .44) or the VAS (80.6% vs 75.0%, respectively; P = .83). Conclusion: Double-row suture bridge rotator cuff repair using all-suture anchors for medial-row fixation demonstrated similar excellent clinical outcomes to rotator cuff repair using solid medial-row anchors.

"Polytopal Rearrangement Model of Stereoisomerization" and Its Potential as the Basis for a Systematic Model of All Stereoisomerism.

The term "polytopal rearrangement" describes any shape changing process operating on a coordination "polyhedron"-the solid figure defined by the positions of the ligand atoms directly attached to the central atom of a coordination entity. Developed in the latter third of the last century, the polytopal rearrangement model of stereoisomerization is a general mathematical approach for analyzing and accommodating the complexity of such processes for any coordination number. The motivation for the model was principally to deal with the complexity, such as Berry pseudorotation in pentavalent phosphorus species, arising from rearrangements in inorganic coordination complexes of higher coordination numbers. The model is also applicable to lower coordination centers, for example, thermal "inversion" at nitrogen in NH3 and amines. We present the history of the model focusing on its essential features, and review some of the more subtle aspects addressed in recent literature. We then introduce a more detailed and rigorous modern approach for describing such processes using an assembly of existing concepts, with the addition of formally described terminology and representations. In our outlook, we contend that the rigorous and exhaustive application of the principles of the polytopal rearrangement model, when combined with torsional isomerism, will provide a basis for a mathematically complete, general, and systematic classification for all stereoisomerism and stereoisomerization. This is essential for comprehensively mapping chemical structure and reaction spaces.