Long-term safety of lentiviral or gammaretroviral gene-modified T cell therapies.

Long-term risks of gene therapy are not fully understood. In this study, we evaluated safety outcomes in 783 patients over more than 2,200 total patient-years of observation from 38 T cell therapy trials. The trials employed integrating gammaretroviral or lentiviral vectors to deliver engineered receptors to target HIV-1 infection or cancer.

Characterization of the Titanium(III) Tris(alkyl) Ti{CH(SiMe3)2}3 and its Conversion to a Dimeric Alkyl-bridged Titanium(IV) Species.

The reaction of three equivalents of LiCH(SiMe3)2 with TiCl3(NMe3)2 afforded the rare homoleptic Ti(III) alkyl Ti{CH(SiMe3)2}3 (1) which crystallized as blue needles in 32 % yield. Single crystal X-Ray data for 1 showed a trigonal pyramidal coordination geometry around titanium, which could be ascribed to weak interactions between the C-H bonds and the Ti(III) atom based on computational results. X-band EPR spectroscopy give spectral parameters consistent with the proposed Ti(III) formulation.

Advancing precision psychiatry and targeted treatments: Insights from immunopsychiatry.

Despite tremendous advancements in neuroscience, there has been limited impact on patient care. Current psychiatric treatments are largely non-specific, and drug development is hindered by outdated, overinclusive diagnostic categories and a "one-size-fits-all" approach. Additionally, mechanisms underlying psychiatric illnesses and their treatments with conventional medications remain poorly understood.

The impact of highly effective modulator therapy on sinusitis and dysosmia in young children with cystic fibrosis: a prospective study protocol.

Background: Chronic rhinosinusitis (CRS) and olfactory dysfunction (OD) are prevalent disease complications in people with cystic fibrosis. These understudied comorbidities significantly impact quality of life. The impact of highly effective modulator therapy (HEMT) in young children with cystic fibrosis (YCwCF) on these disease complications is unknown.

Electron transfer in polysaccharide monooxygenase catalysis.

Polysaccharide monooxygenase (PMO) catalysis involves the chemically difficult hydroxylation of unactivated C-H bonds in carbohydrates. The reaction requires reducing equivalents and will utilize either oxygen or hydrogen peroxide as a cosubstrate. Two key mechanistic questions are addressed here: 1) How does the enzyme regulate the timely and tightly controlled electron delivery to the mononuclear copper active site, especially when bound substrate occludes the active site? and 2) How does this electron delivery differ when utilizing oxygen or hydrogen peroxide as a cosubstrate? Using a computational approach, potential paths of electron transfer (ET) to the active site copper ion were identified in a representative AA9 family PMO from (PMO9E).

Microwave-Assisted Synthesis of Heterocycles via Rhodium(III)-Catalyzed C-H Activation: Norbornadiene as an Acetylene Equivalent.

General procedures for the rhodium-catalyzed annulation of aryl/heteroaryl -pivaloyl hydroxamic acids and norbornadiene have been developed. Employing norbornadiene as an acetylene equivalent enables utilization of diverse heterocyclic substrates for this transformation which fail to react or undergo competitive Lossen rearrangement under previously reported conditions. Microwave heating significantly reduces reaction times compared to conventional protocols and allows a one-step process to be realized.

Dynamic supramolecular snub cubes.

Mimicking the superstructures and properties of spherical biological encapsulants such as viral capsids and ferritin offers viable pathways to understand their chiral assemblies and functional roles in living systems. However, stereospecific assembly of artificial polyhedra with mechanical properties and guest-binding attributes akin to biological encapsulants remains a formidable challenge. Here we report the stereospecific assembly of dynamic supramolecular snub cubes from 12 helical macrocycles, which are held together by 144 weak C-H hydrogen bonds.

Plasma Microbial Cell-Free DNA Sequencing for Diagnosis of Pediatric Lyme Disease.

We conducted an exploratory study of plasma microbial cell-free DNA sequencing for the diagnosis of Lyme disease among pediatric patients. Low levels of Borrelia burgdorferi microbial cell-free DNA (<3-5 molecules per microliter) were observed in 6/9 serologically confirmed participants, including 4/5 with arthritis and 2/3 with multiple erythema migrans.

Non-Canonical Cytochrome P450 Enzymes in Nature.

Cytochrome P450s (CYPs) are a superfamily of thiolate-ligated heme metalloenzymes principally responsible for the hydroxylation of unactivated C-H bonds. The lower-axial cysteine is an obligatory and universally conserved residue for the CYP enzyme class. Herein, we challenge this paradigm by systematically identifying non-canonical CYPs (ncCYPs) that do not harbor a cysteine ligand.

Propensity Score Analysis of Possible Medication Effects on Outcomes in Patients With Systemic Right Ventricles.

Background: Patients with systemic right ventricle (SRV), either d-transposition of the great arteries following an atrial switch procedure or congenitally corrected transposition of the great arteries, develop severe right ventricular dysfunction, prompting appropriate medical therapy. However, the efficacy of beta-blockers and angiotensin receptor blockers or angiotensin-converting enzyme inhibitors (ACEI) in SRV patients is unproven.

Objectives: The objective of this study was to determine the effects of ACEI/ARB and beta-blockers on outcomes in SRV patients after accounting for likely cofounders affecting their use.

O Activation and Enzymatic C-H Bond Activation Mediated by a Dimanganese Cofactor.

Dioxygen (O) is a potent oxidant used by aerobic organisms for energy transduction and critical biosynthetic processes. Numerous metalloenzymes harness O to mediate C-H bond hydroxylation reactions, but most commonly feature iron or copper ions in their active site cofactors. In contrast, many manganese-activated enzymes─such as glutamine synthetase and isocitrate lyase─perform redox neutral chemical transformations and very few are known to activate O or C-H bonds.

Univariate Prediction of Hammett Parameters and Select Relative Reaction Rates Using Loewdin Atomic Charges.

Loewdin charges from density functional theory calculations were used here to obtain general, univariate linear correlations for the prediction of experimental Hammett parameters and relative reaction rates. While previous studies have established that Hirshfeld and CM5 charges perform strongly as univariate predictors, the near-ubiquitous Loewdin charges have not yet been evaluated. To this end, we assess the predictive capability of Loewdin charges for three chemical systems.

C-H Bond Activation by Sulfated Zirconium Oxide is Mediated by a Sulfur-Centered Lewis Superacid.

Sulfated zirconium oxide (SZO) catalyzes the hydrogenolysis of isotactic polypropylene (iPP, M=13.3 kDa, Đ=2.4, =94 %) or high-density polyethylene (HDPE, M=2.

Human AI collaboration for unsupervised categorization of live surgical feedback.

Formative verbal feedback during live surgery is essential for adjusting trainee behavior and accelerating skill acquisition. Despite its importance, understanding optimal feedback is challenging due to the difficulty of capturing and categorizing feedback at scale. We propose a Human-AI Collaborative Refinement Process that uses unsupervised machine learning (Topic Modeling) with human refinement to discover feedback categories from surgical transcripts.

Changes in DNA methylation are associated with systemic lupus erythematosus flare remission and clinical subtypes.

Background: Systemic lupus erythematosus (SLE) has numerous symptoms across organs and an unpredictable flare-remittance pattern. This has made it challenging to understand drivers of long-term SLE outcomes. Our objective was to identify whether changes in DNA methylation over time, in an actively flaring SLE cohort, were associated with remission and whether these changes meaningfully subtype SLE patients.

High-Valent Cobalt-Difluoride in Oxidative Fluorination of Saturated Hydrocarbons.

The heme paradigm where Fe=O acts as the C-H oxidant and Fe-OH rebounds with the formed carbon-centered radical guides the design of the prototypical synthetic hydroxylation catalyst. We are exploring methods to evolve beyond the metal-oxo oxidant and hydroxide rebound, to incorporate a wider array of functional group. We have demonstrated the application of Co(OTf) (10 mol% catalyst; OTf=trimfluoromethanesulfonate) in combination with polydentate N-donor ligands (e.

Palovarotene (Sohonos), a synthetic retinoid for reducing new heterotopic ossification in fibrodysplasia ossificans progressiva: history, present, and future.

Retinoids are metabolic derivatives of vitamin A and play crucial roles in the regulation of various tissues and organs during prenatal and postnatal development. Active retinoids, like all-trans-retinoic acid, are synthesized in the cytoplasm and subsequently interact with nuclear retinoic acid receptors (RARα, RARβ, and RARγ) to enhance transcription of specific genes. In the absence of retinoids, RARs can still bind to response elements of target genes but repress their transcription.

Mesoscale functional architecture in medial posterior parietal cortex.

The posterior parietal cortex () in mice has various functions including multisensory integration, vision-guided behaviors, working memory, and posture control. However, an integrated understanding of these functions and their cortical localizations in and around the PPC and higher visual areas (), has not been completely elucidated. Here we simultaneously imaged the activity of thousands of neurons within a 3 × 3 mm field-of-view, including eight cortical areas around the PPC, during behavior with a two-photon mesoscope.

Prospective Evaluation of Clinical Outcomes of the Subchondroplasty Procedure for Treatment of Symptomatic Bone Marrow Lesions of the Knee.

Bone marrow lesions (BMLs) have a strong correlation to patient-reported pain, functional limitations, joint deterioration, and rapid progression to total knee arthroplasty. The Subchondroplasty (SCP) procedure uses AccuFill, a calcium phosphate bone substitute material (BSM), to treat bone defects such as microtrabecular fractures and BML. This observational, prospective, multicenter, cohort study evaluated the effect of the SCP procedure at the 2-year follow-up for 70 patients with knee BML.

Assembly of the Tricyclic Core of Alopecurone C by Asymmetric Donor/Donor Carbene C-H Insertion.

Two routes to assemble the complete tricyclic core of alopecurone C are described. In the first-generation route, an efficient synthesis of the "eastern" half of the target, including a decagram-scale rhodium-catalyzed C-H insertion reaction, was developed. When this route proved intractable for assembling the final flavanone ring, a successful second-generation route was developed from a flavanone precursor (naringenin) employing a later stage C-H insertion.

Evidence-based guideline: premature ovarian insufficiency.

Study Question: How should premature/primary ovarian insufficiency (POI) be diagnosed and managed based on the best available evidence from published literature?

Summary Answer: The current guideline provides 145 recommendations on symptoms, diagnosis, causation, sequelae, and treatment of POI.

What Is Known Already: Premature ovarian insufficiency (POI) presents a significant challenge to women's health, with far-reaching implications, both physically and emotionally. The potential implications include adverse effects on quality of life; fertility; and bone, cardiovascular, and cognitive health.

Clinical Use of Home OCT Data to Manage Neovascular Age-Related Macular Degeneration.

To investigate how home optical coherence tomography (OCT) influences the clinical decision-making of retina specialists for the management of neovascular age-related macular degeneration (nAMD). In this retrospective imaging review, 15 retina specialists each evaluated 10 home OCT data segments from 29 eyes being treated for nAMD. Based on OCT data, indications were identified for when eyes should be treated, which antivascular endothelial growth factor should be used, and the specific retinal fluid and time thresholds for notification.

Evidence-based guideline: Premature Ovarian Insufficiency.

Study Question: How should premature/primary ovarian insufficiency (POI) be diagnosed and managed, based on the best available evidence from published literature?

Summary Answer: The current guideline provides 145 recommendations on symptoms, diagnosis, causation, sequelae and treatment of POI.

What Is Known Already: Premature ovarian insufficiency (POI) presents a significant challenge to women's health, with far-reaching implications, both physically and emotionally. The potential implications include adverse effects on quality of life; fertility; and bone, cardiovascular and cognitive health.