A Review of Gene Therapies for Hemoglobinopathies.

Due to the significant morbidity and mortality of hemoglobinopathies, curative options have long been pursued. The overall goal of gene therapy is to modify a patient's own hematopoietic stem cells to overcome the deleterious effects of the underlying genetic defect by gene addition, gene editing, or gene silencing. Gene addition incorporates genes with superior function than the abnormal gene; gene editing takes advantage of molecular tools such as zinc finger proteins, Transcription Activator-Like Effector Nucleases and Clustered Regularly Interspaced Short Palindromic Repeats coupled with Cas9 proteins (CRISPR-Cas9) which allow for sequence-specific breaks in DNA that disrupt gene function; and gene silencing suppresses gene expression by interference with mRNA transcription/protein translation or epigenetic modification. The majority of gene therapy strategies for hemoglobinopathies have targeted erythroid-specific BCL11A, a major regulator of fetal hemoglobin repression at the gamma-globin locus, in the normal fetal-to-adult hemoglobin switch that occurs shortly after birth. Other goals have involved the incorporation of anti-sickling globins, such as ßT87Q or ßAS3. Landmark clinical trials of gene therapy in transfusion-dependent thalassemia and sickle cell disease have shown remarkable efficacy and acceptable safety and culminated in recent regulatory approvals of gene therapy for both diseases in Europe and the United States.

Insight from Electrochemical Analysis in the Radical Cation State of a Monopyrrolotetrathiafulvalene Based [2]Rotaxane.

Mechanically interlocked molecules are a class of compounds used for controlling directional movement when barriers can be raised and lowered using external stimuli. Applied voltages can turn on redox states to alter electrostatic barriers but their use for directing motion requires knowledge of their impact on the kinetics. Herein, we make the first measurements on the movement of cyclobis(paraquat-p-phenylene) (CBPQT4+) across the radical-cation state of monopyrrolotetrathiafulvalene (MPTTF) in a [2]rotaxane using variable scan-rate electrochemistry. The [2]rotaxane is designed in a way that directs CBPQT4+ to a high-energy co-conformation upon oxidation of MPTTF to either the radical cation (MPTTF•+) or the dication (MPTTF2+). 1H NMR spectroscopic investigations carried out in acetonitrile at 298 K showed direct interconversion to the thermodynamically more stable ground-state co-conformation with CBPQT4+ moving across the oxidized MPTTF2+ electrostatic barrier. The electrochemical studies revealed that interconversion takes place by movement of CBPQT4+ across both the MPTTF•+ (19.3 kcal mol-1) and MPTTF2+ (18.7 kcal mol-1) barriers. The outcome of our studies shows that MPTTF has three accessible redox states that can be used to kinetically control the movement of the ring component in mechanically interlocked molecules.

Cone Angles Quantify and Predict the Affinity and Reactivity of Anion Complexes between Trifluoroborates and Rigid Macrocycles.

Steric manipulation is a known concept in molecular recognition but there is currently no linear free energy relationship correlating sterics to the stability of receptor-anion complexes nor to the reactivity of the bound anion. By analogy to Tolman cone angles in cation coordination chemistry, we explore how to define and correlate cone angles of organo-trifluoroborates (R-BF3 -) to the affinities observed for cyanostar-anion binding. We extend the analogy to a rare investigation of the anion's reactivity and how it changes upon binding. The substituent on the anion is used to define the cone angle, θ. A series of 10 anions were studied including versions with ethynyl, ethylene, and ethyl substituents to tune steric bulk across the sp, sp2 and sp3 hybridized α-carbons bearing 0, 1 and 2 hydrogen atoms. A linear relationship between affinity and cone angle is observed for anions bearing substituents larger than the -BF3 - headgroup. This correlation predicted affinities of two new anions to within ±5 %. We explored how complexation affects the reactivity of fluoride exchange. The yield of fluoride transfer from R-BF3 - to Lewis acid triphenylborane is correlated with cone angle. We predict that other rigid macrocycles, like commercially available bambusuril, could follow these trends.

Active infection at the time of CD34+ selected stem cell boost is associated with treatment failure and poor survival.

BACKGROUND: The use of CD34+ selected stem cell boost (SCB) post allogeneic hematopoietic cell transplant (alloHCT) has been increasing. Predictors of treatment failure following SCB, both in the context of poor graft function (PGF) or other settings, are not well-characterized. We report among the largest single center retrospective experiences of the use of SCB and evaluate potential predictors of response and outcomes. METHODS: 58 patients who underwent HCT between 2015 and 2022 and who received SCB were identified. The indication for SCB was predominantly PGF, defined as the presence of 2 or more cytopenias for at least two consecutive weeks beyond day +14 after alloHCT in the presence of ≤ 30% bone marrow cellularity and ≥ 90% donor myeloid chimerism in the absence of morphological disease. RESULTS: The median dose of infused CD34+ selected SCB products was 3.88 x 106 CD34+ cells/kg (range: 0.99-9.92). The median 2-year OS and NRM following SCB was 47% and 38%, respectively. The cumulative incidences of 6-month grade III-IV acute and 2-year moderate-severe chronic GVHD following SCB were 3.4% and 12%, respectively. Overall response (CR + PR) was attained in 36/58 (62%) patients, and in 69% with PGF. On multivariable analysis, an active infection at the time of SCB was the greatest predictor of poor response and survival (p=0.013) following SCB. CONCLUSION: SCB can restore hematopoiesis in the majority of patients, particularly for those with poor graft function in whom there is no active infection at infusion.

Direct Writing of Room Temperature Polariton Condensate Lattice.

Realizing lattices of exciton polariton condensates has been of much interest owing to the potential of such systems to realize analogue Hamiltonian simulators and physical computing architectures. Here, we report the realization of a room temperature polariton condensate lattice using a direct-write approach. Polariton condensation is achieved in a microcavity embedded with host-guest Frenkel excitons of an organic dye (rhodamine) in a small-molecule ionic isolation lattice (SMILES). The microcavity is patterned using focused ion beam etching to realize arbitrary lattice geometries, including defect sites on demand. The band structure of the lattice and the emergence of condensation are imaged using momentum-resolved spectroscopy. The introduction of defect sites is shown to lower the condensation threshold and result in the formation of a defect band in the condensation spectrum. The present approach allows us to study periodic, quasiperiodic, and disordered polariton condensate lattices at room temperature using a direct-write approach.

Control of the fluorescence lifetime in dye based nanoparticles.

Fluorescent dye based nanoparticles (NPs) have received increased interest due to their high brightness and stability. In fluorescence microscopy and assays, high signal to background ratios and multiple channels of detection are highly coveted. To this end, time-resolved imaging offers suppression of background and temporal separation of spectrally overlapping signals. Although dye based NPs and time-resolved imaging are widely used individually, the combination of the two is uncommon. This is likely due to that dye based NPs in general display shortened and non-mono-exponential lifetimes. The lower quality of the lifetime signal from dyes in NPs is caused by aggregation caused quenching (ACQ) and energy migration to dark states in NPs. Here, we report a solution to this problem by the use of the small-molecule ionic isolation lattices (SMILES) concept to prevent ACQ. Additionally, incorporation of FRET pairs of dyes locks the exciton on the FRET acceptor providing control of the fluorescence lifetime. We demonstrate how SMILES NPs with a few percent rhodamine and diazaoxatriangulenium FRET acceptors imbedded with a cyanine donor dye give identical emission spectra and high quantum yields but very different fluorescence lifetimes of 3 ns and 26 ns, respectively. The two spectrally identical NPs are easily distinguished at the single particle level in fluorescence lifetime imaging. The doping approach for dye based NPs provides predictable fluorescence lifetimes and allows for these bright imaging reagents to be used in time-resolved imaging detection modalities.

Trends in volumes and survival after hematopoietic cell transplantation in racial/ethnic minorities.

ABSTRACT: There has been an increase in volume as well as an improvement in overall survival (OS) after hematopoietic cell transplantation (HCT) for hematologic disorders. It is unknown if these changes have affected racial/ethnic minorities equally. In this observational study from the Center for International Blood and Marrow Transplant Research of 79 904 autologous (auto) and 65 662 allogeneic (allo) HCTs, we examined the volume and rates of change of autoHCT and alloHCT over time and trends in OS in 4 racial/ethnic groups: non-Hispanic Whites (NHWs), non-Hispanic African Americans (NHAAs), and Hispanics across 5 2-year cohorts from 2009 to 2018. Rates of change were compared using Poisson model. Adjusted and unadjusted Cox proportional hazards models examined trends in mortality in the 4 racial/ethnic groups over 5 study time periods. The rates of increase in volume were significantly higher for Hispanics and NHAAs vs NHW for both autoHCT and alloHCT. Adjusted overall mortality after autoHCT was comparable across all racial/ethnic groups. NHAA adults (hazard ratio [HR] 1.13; 95% confidence interval [CI] 1.04-1.22; P = .004) and pediatric patients (HR 1.62; 95% CI 1.3-2.03; P < .001) had a higher risk of mortality after alloHCT than NHWs. Improvement in OS over time was seen in all 4 groups after both autoHCT and alloHCT. Our study shows the rate of change for the use of autoHCT and alloHCT is higher in NHAAs and Hispanics than in NHWs. Survival after autoHCT and alloHCT improved over time; however, NHAAs have worse OS after alloHCT, which has persisted. Continued efforts are needed to mitigate disparities for patients requiring alloHCT.

Vaccination of Adults With Cancer: ASCO Guideline.

PURPOSE: To guide the vaccination of adults with solid tumors or hematologic malignancies. METHODS: A systematic literature review identified systematic reviews, randomized controlled trials (RCTs), and nonrandomized studies on the efficacy and safety of vaccines used by adults with cancer or their household contacts. This review builds on a 2013 guideline by the Infectious Disease Society of America. PubMed and the Cochrane Library were searched from January 1, 2013, to February 16, 2023. ASCO convened an Expert Panel to review the evidence and formulate recommendations. RESULTS: A total of 102 publications were included in the systematic review: 24 systematic reviews, 14 RCTs, and 64 nonrandomized studies. The largest body of evidence addressed COVID-19 vaccines. RECOMMENDATIONS: The goal of vaccination is to limit the severity of infection and prevent infection where feasible. Optimizing vaccination status should be considered a key element in the care of patients with cancer. This approach includes the documentation of vaccination status at the time of the first patient visit; timely provision of recommended vaccines; and appropriate revaccination after hematopoietic stem-cell transplantation, chimeric antigen receptor T-cell therapy, or B-cell-depleting therapy. Active interaction and coordination among healthcare providers, including primary care practitioners, pharmacists, and nursing team members, are needed. Vaccination of household contacts will enhance protection for patients with cancer. Some vaccination and revaccination plans for patients with cancer may be affected by the underlying immune status and the anticancer therapy received. As a result, vaccine strategies may differ from the vaccine recommendations for the general healthy adult population vaccine.Additional information is available at www.asco.org/supportive-care-guidelines.

Epidemiology and patterns of gymnastics-related head & neck trauma injuries: A NEISS database study.

OBJECTIVE: To describe the epidemiology and patterns of gymnastics-related Head & Neck trauma injuries using the NEISS database from 2001 to 2020. STUDY DESIGN AND SETTING: Cross-sectional analysis of a national database. METHODS: Gymnastics-related ED visits between 2001 and 2020 were queried from the NEISS database. Bivariate chi-squared analyses were used to compare injury demographics, location, type, and disposition. Fracture location was identified using the narrative description of each case and were divided into subtypes for further analysis. RESULTS: 1455 gymnastics-related head and neck traumatic injuries were identified. The majority were in females (65.8%). The most common presenting age group was pediatric (≤18 years) (92.7%), and the largest racial group was Caucasian (51.5%). Of all location subtypes, facial injuries were the most common presenting injury type overall (45.2%). Regarding injury types, lacerations were most common (36.8%), followed by dental injury (30.7%) and fractures (21.2%). The most common location of head and neck fractures was the nose (45.8%), followed by cervical spine (16.7%) and orbit (13.3%). The majority (95.7%) of gymnastics-related head and neck traumatic injuries presenting to the ED were treated and discharged. CONCLUSION: This study characterizes gymnastics-related head and neck injuries which is a topic that is under-studied. The findings from this study are helpful for gymnasts and those who care for them including providers, coaches and guardians, and this data may help inform future guidelines for treatment and injury prevention.

Solvent-Dependent Folding Behavior of a Helix-Forming Aryl-Triazole Foldamer.

Aromatic foldamers make up a novel class of bioinspired molecules that display helical conformations and have functions that rely on control over their coil-helix folding preferences. While the folding has been extensively examined by experiment, it has rarely been paired with the types of atomic level insights offered by theory. We present the results of all-atom molecular dynamics (MD) simulations to examine the role of solvent polarity on driving the helical folding behavior of the aryl-triazole foldamer. The temperature-dependent enhanced sampling technique, replica-exchange MD simulations, was employed to understand the folding phenomena. The simulation results show that in a low polarity solvent (dichloromethane), the foldamer prefers to stay in the unfolded state. The unfolded state has four dipolar triazoles (5 D) in their favored all-anti geometries and favoring anti-parallel geometries. However, an increase in solvent polarity using acetonitrile resulted in solvophobic collapse, yielding the helically folded form as the predominant state. The folded helix has an all-syn geometry, with triazoles in parallel arrangements. Intermediate conformations with a mixture of syn and anti arrangements of the triazoles are of lower abundance in both the DCM and MeCN solvents. The chiral handedness of the helix observed experimentally is assigned as left-handed by correlation with computed electronic circular dichroism spectra using time-dependent density functional theory.

Is Public Interest Associated with Real-World Management of Ankyloglossia?

OBJECTIVES: Assess the relationship between public interest in ankyloglossia as determined by internet search volume and real-world medical claims data. STUDY DESIGN: Retrospective Cohort Study. SETTING: This retrospective cohort study was conducted using claims data from the Merative™ Marketscan® Research Databases. The internet search data was collected from Google Trends. METHODS: Annual Google Trends data were compiled using search terms associated with "ankyloglossia" and "frenotomy" for the years 2011 to 2021. We obtained incidence of ankyloglossia diagnoses and frenotomy procedures in children under 12 months from Marketscan relative to all infants enrolled. We compared associations between search and incidence data among US states and over time. RESULTS: Google search correlated with ankyloglossia incidence (r = 0.4104, P = .0031) and with frenotomy incidence (r = 0.4062, P = .0034) per state. Ankyloglossia diagnoses increased with Google search index (coefficient = 0.336, 95% confidence interval [CI] 0.284, 0.388) and year (coefficient = 0.028, 95% CI 0.025, 0.031). Similarly, frenotomy procedures increased with Google search index (coefficient = 0.371, 95% CI 0.313, 0.429) and year (coefficient = 0.027, 95% CI 0.024, 0.030). CONCLUSIONS: Associations between online ankyloglossia search trends and both diagnosis and treatment rates, persist across US regions and timeframes. Internet search trends are pivotal in shaping pediatric health care decisions, driving clinical consensus, and disseminating evidence-based information.

The Prevalence, Severity and Pattern of First Permanent Molars’ Dental Caries in Children Attending A Postgraduate Dental Hospital: A Retrospective Study

@#Introduction: First permanent molars (FPMs) erupt early and their anatomy and location leave them susceptible to dental caries. This study aimed to retrospectively determine the prevalence, severity and pattern of dental caries of FPMs and investigate their relationship if any with demographics and medical health status of the partcipants. Methods: This was a retrospective cross-sectional study. A sample of the digital case notes and radiographs of children aged 5 to 12 years who attended the only postgraduate dental hospital in Dubai were accessed. The recorded data included the children’s demographic variables and the carious status of each FPM as recorded in the notes on the initial assessment. Descriptive and statistical analyses were conducted (P<0.05). Results: A total of 2984 FPMs were obtained from the digital records of 774 children. Their mean age was 8.07 (±2.23) years and only those that met the inclusion criteria were included in the study. The prevalence of dental caries and mean Decayed Missing Filled Surfaces of FPMs, were 42% and 0.3 (±0.04), respectively. The most prevalent decayed surface was the occlusal (29.2%), followed by mesial, buccal, palatal/ lingual, distal surfaces (24.2 %; 6.6 %; 3.1 %; 2.3 %) respectively. Children with medical problems and/or special needs had a significantly higher level of caries in the buccal surfaces (12.3%) (P=0.042). Conclusion: Caries of FPMs in a sample of Dubai children studied was prevalent, especially in those with special healthcare needs, thus indicating a necessity for targeted prevention and treatment focused on these keystone teeth.

A library of vinyl phosphonate anions dimerize with cyanostars, form supramolecular polymers and undergo statistical sorting.

Supramolecular dimers are elementary units allowing the build-up of multi-molecule architectures. New among these are cyanostar-stabilized dimers of phosphate and phosphonate anions. While the anion dimerization at the heart of these assemblies is reliable, the covalent synthesis leading to this class of designer anions serves as a bottleneck in the pathway to supramolecular assemblies. Herein, we demonstrate the reliable synthesis of 14 diverse anionic monomers by Heck coupling between vinyl phosphonic acid and aryl bromide compounds. When this synthesis is combined with reliable anion dimerization, we show formation of supramolecular dimers and polymers by co-assembly with cyanostar macrocycles. The removal of the covalent bottleneck opened up a seamless synthetic route to iterate through three monomers affording the solubility needed to characterize the mechanism of supramolecular polymerization. We also test the idea that the small size of these vinyl phosphonates provide identical dimer stabilities across the library by showing how mixtures of anions undergo statistical (social) self-sorting. We exploit this property by preparing soluble copolymers from the mixing of different monomers. This multi-anion assembly shows the utility of a library for programming properties.

The Effect of Chlorhexidine on Bacterial Contamination of Hall Technique Elastomeric Orthodontic Separators and Gingival Health: A Pilot Study

ABSTRACT Objective: To study the effect of chlorhexidine on elastomeric orthodontic separators (EOS) bacterial-colonisation and gingival-health in Hall technique (HT) patients. Material and Methods: Prospective in-vivo pilot clinical study of EOS bacterial colonisation and primary-molar gingival health assessment in 20 patients (mean age 5.45±1.27 years) requiring bilateral HT crowns (40 teeth). One side received 1-minute 0.12% chlorhexidine-soaked-EOSs (Chx-EOSs), and the other side dry-EOSs (NoChx-EOSs). The EOSs were removed five-days later and underwent a bacterial enumeration technique. Plaque (PI) and Gingival (GI) indices were assessed pre-, five-days and three-months post-treatment. Wilcoxon-Signed-Rank/McNemar-Chi-square statistics were used (p<0.05). Results: Baseline unused/packaged EOSs' sterility check yielded zero colony-forming-units (CFU) per millilitre, but 100% of the used EOSs became colonised by oral-microorganisms. An overall trend of lower mean CFU count in Chx-EOSs (3.415± 0.78 x105 CFU/ml) compared to NoChx-EOSs (6.157±1.48 x105 CFU/ml) was observed (p=0.009). Both NoChx-EOSs and Chx-EOSs insertion sites showed evidence of gingivitis with no difference between PI and GI indices by site over time. Conclusion: There was a lower trend of bacterial colonization in chlorhexidine treated EOSs and an occurrence of gingivitis pre/post HT-treatment regardless of EOS type. The lack of difference in the gingival health may be inconclusive due to this pilot's low power suggesting the need for robust large scale studies.

Clinical Variables Correlate with Serum Neutralizing Antibody Titers after COVID-19 mRNA Vaccination in an Adult, US-based Population

BackgroundWe studied whether comorbid conditions impact strength and duration of immune responses after SARS-CoV-2 mRNA vaccination in a US-based, adult population. MethodsSera (pre-and-post-BNT162b2 vaccination) were tested serially up to 12 months after two doses of vaccine for SARS-CoV-2-anti-Spike neutralizing capacity by pseudotyping assay in 124 individuals; neutralizing titers were correlated to clinical variables with multivariate regression. Post-booster (third dose) effect was measured at 1 and 3 months in 72 and 88 subjects respectively. ResultsAfter completion of primary vaccine series, neutralizing antibody IC50 values were high at one month (14-fold increase from pre-vaccination), declined at six months (3.3-fold increase), and increased at one month post-booster (41.5-fold increase). Three months post-booster, IC50 decreased in COVID-naive individuals (18-fold increase) and increased in prior COVID-19+ individuals (132-fold increase). Age >65 years ({beta}=-0.94, p=0.001) and malignancy ({beta}=-0.88, p=0.002) reduced strength of response at 1 month. Both strength and durability of response at 6 months, respectively, were negatively impacted by end-stage renal disease [({beta}=-1.10, p=0.004); ({beta}=-0.66, p=0.014)], diabetes mellitus [({beta}=-0.57, p=0.032); ({beta}=-0.44, p=0.028)], and systemic steroid use [({beta}=-0.066, p=0.032); ({beta}=-0.55, p=0.037)]. Post-booster IC50 was robust against WA-1 and B.1.617.2, but the immune response decreased with malignancy ({beta} =-0.68, p=0.03) and increased with prior COVID-19 (p-value < 0.0001). ConclusionMultiple clinical factors impact the strength and duration of neutralization response post-primary series vaccination, but not the post-booster dose strength. Prior COVID-19 infection enhances the booster-dose response except in individuals with malignancy, suggesting a need for clinically guiding vaccine dosing regimens. SummaryMultiple clinical factors impact the strength and duration of neutralization response post-primary series vaccination. All subjects, irrespective of prior COVID infection, benefited from a third dose. Malignancy decreased response following third dose, suggesting the importance of clinically guided vaccine regimens.