Differences in Positive Airway Pressure Requirements in Obstructive Sleep Apnea Between Black and White Patients.

OBJECTIVE: There are disparities between Black and White patients in the utilization of positive airway pressure (PAP) alternatives for obstructive sleep apnea (OSA). Given low utilization rates among Black patients, there is limited knowledge of PAP alternative outcomes in this group. Therapeutic PAP levels are clinically accessible measures that have been shown to predict PAP alternative outcomes. Herein, we examined differences in PAP requirements between Black and White patients in a large clinical sample. STUDY DESIGN: Cross-sectional. SETTING: Academic sleep center. METHODS: We included OSA patients prescribed autoadjusting PAP between January 2018 and 2020 with baseline apnea-hypopnea index (AHI) ≥ 10. Mean and 90th percentile PAP levels were compared between White and Black patients who used PAP for ≥1 hour daily using linear regression controlling for age, sex, body mass index (BMI), AHI, oxygen saturation nadir, and mask type. RESULTS: There were 157 Black and 234 White patients who were generally obese (BMI, 37.3 ± 8.7) with severe OSA (AHI, 36.9 ± 25.6). Black patients had a 0.68 cm higher (95% confidence interval [CI]: 0.36, 1.35) mean PAP level and 0.85 cm H2O higher (95% CI: 0.36, 1.35) 90th percentile PAP level than white patients. Although statistically significant, differences were small and not clinically meaningful. CONCLUSION: Black and White OSA patients had clinically insignificant differences in PAP requirements, suggesting comparable upper airway collapsibility. Considering the predictive value of therapeutic PAP levels, our findings suggest Black and White patients may have comparable PAP alternative responses from a collapsibility standpoint. Future studies should explore reasons for low utilization of PAP alternatives among Black patients.

The Repeatability of Pharyngeal Opening Pressure Under Drug-Induced Sleep Endoscopy.

OBJECTIVE: Pharyngeal opening pressure (PhOP) is a measure of upper airway collapsibility that can be obtained during drug-induced sleep endoscopy (DISE) using a continuous positive airway pressure (CPAP) titration. However, the stability of PhOP over the course of sedation during DISE remains unclear. This study aims to compare repeat measures of PhOP over the course of DISE. STUDY DESIGN: Single arm prospective study. SETTING: Single tertiary care institution. METHODS: Patients had 2 CPAP titrations while undergoing DISE. Collected data included patient demographics, PhOP, patient sedation index (PSI), and duration of and between CPAP titrations. t Tests, test-retest coefficient analysis, and repeated measures correlation were performed. RESULTS: Twenty-five patients completed the study between 2022 and 2023 with 22 patients having sedation depth (PSI) recording. Most were male (76%), obese (average body mass index: 30.24 kg/m2), with severe obstructive sleep apnea (average apnea-hypopnea index: 39.8 events/hr). Test-retest analysis showed good-excellent correlation between PhOP values (intraclass correlation coefficient = 0.892, P < .0001, n = 25). Average time between CPAP titrations was 15 minutes to 6 seconds. Over that time, PhOP increased by an average of 0.72 cmH2O (P = .06, n = 25) and PSI decreased by 9.5 units (P = .01, n = 22). Repeated measures correlation showed a weak negative correlation between PhOP and PSI (r = -.45, P = .03, n = 22). CONCLUSION: The results showed repeatability of PhOP values over the course of DISE. When adjusted for sedation depth (PSI), deeper sedation was weakly associated with greater PHOP. However, the magnitude of this change was small and we conclude that PhOP remains relatively stable over the course of DISE (Effects of Lung Volume on Upper Airway Patency During DISE [DISE-Pulm], NCT05350332, clinicaltrials.gov).

The use of flaps for management of deep sternal wound complications: A systematic review and meta-analysis.

BACKGROUND: Many options are available for reconstruction after deep sternal wound infections. However, these options have not been critically appraised. The aim of this systematic review and meta-analysis was to assess the existing evidence on sternal rewiring versus flap reconstruction and pectoralis major muscle flaps (PMFs) versus greater omental flaps (GOFs). METHODS: A systematic review and meta-analysis was performed. CENTRAL, MEDLINE and EMBASE were searched. Outcomes of interest included mortality, treatment failure and length of hospital stay (LOS). RESULTS: Fourteen studies were included. Nine studies compared flaps to rewiring, reporting on 618 patients. Patients treated with flaps had significantly lower mortality compared with patient treated with rewiring (Risk ratio [RR] 0.42, 95% confidence interval [CI]: 0.23-0.77, P < 0.01). Flap patients had significantly lower treatment failure compared with those who were treated with rewiring (RR 0.22, 95% CI: 0.14-0.37, P < 0.01). No statistically significant differences were observed in LOS between patients treated with flaps compared those treated with rewiring (standard mean difference -0.84, 95% CI: -1.91 to 0.24, P = 0.13). Five studies compared PMF with GOF, reporting on 599 patients. No statistically significant differences were found in mortality (RR 0.63, 95% CI: 0.24-1.68, P = 0.36), LOS (standard mean difference -14.52, 95% CI: -42.00 to 12.96, P = 0.30) or treatment failure (RR 1.37, 95% CI: 0.31-6.07, P = 0.68) in patients treated with PMF compared with patients treated with GOF. CONCLUSIONS: Flap-based reconstruction demonstrated improved mortality and treatment outcomes compared to sternal rewiring. However, no significant differences were observed in outcomes between the PMF- and GOF-based reconstructions.

Dehazing Ultrasound using Diffusion Models.

Echocardiography has been a prominent tool for the diagnosis of cardiac disease. However, these diagnoses can be heavily impeded by poor image quality. Acoustic clutter emerges due to multipath reflections imposed by layers of skin, subcutaneous fat, and intercostal muscle between the transducer and heart. As a result, haze and other noise artifacts pose a real challenge to cardiac ultrasound imaging. In many cases, especially with difficult-to-image patients such as patients with obesity, a diagnosis from B-Mode ultrasound imaging is effectively rendered unusable, forcing sonographers to resort to contrast-enhanced ultrasound examinations or refer patients to other imaging modalities. Tissue harmonic imaging has been a popular approach to combat haze, but in severe cases is still heavily impacted by haze. Alternatively, denoising algorithms are typically unable to remove highly structured and correlated noise, such as haze. It remains a challenge to accurately describe the statistical properties of structured haze, and develop an inference method to subsequently remove it. Diffusion models have emerged as powerful generative models and have shown their effectiveness in a variety of inverse problems. In this work, we present a joint posterior sampling framework that combines two separate diffusion models to model the distribution of both clean ultrasound and haze in an unsupervised manner. Furthermore, we demonstrate techniques for effectively training diffusion models on radio-frequency ultrasound data and highlight the advantages over image data. Experiments on both in-vitro and in-vivo cardiac datasets show that the proposed dehazing method effectively removes haze while preserving signals from weakly reflected tissue.

Natural determinant reference functional theory.

The natural determinant reference (NDR) or principal natural determinant is the Slater determinant comprised of the N most strongly occupied natural orbitals of an N-electron state of interest. Unlike the Kohn-Sham (KS) determinant, which yields the exact ground-state density, the NDR only yields the best idempotent approximation to the interacting one-particle reduced density matrix, but it is well-defined in common atom-centered basis sets and is representation-invariant. We show that the under-determination problem of prior attempts to define a ground-state energy functional of the NDR is overcome in a grand-canonical ensemble framework at the zero-temperature limit. The resulting grand potential functional of the NDR ensemble affords the variational determination of the ground state energy, its NDR (ensemble), and select ionization potentials and electron affinities. The NDR functional theory can be viewed as an "exactification" of orbital optimization and empirical generalized KS methods. NDR functionals depending on the noninteracting Hamiltonian do not require troublesome KS-inversion or optimized effective potentials.

Posterior Palatal Expansion via Subnasal Endoscopy (2PENN) for Maxillary Deficiency: A Pilot Study.

OBJECTIVE: Surgically assisted rapid palatal expansion (SARPE) addresses transverse maxillary deficiency, a known contributor to nasal obstruction. The purpose of this study was to assess the feasibility, preliminary outcomes, and safety of posterior palatal expansion via subnasal endoscopy (2PENN), a modified SARPE procedure, aimed at achieving anterior and posterior maxillary expansion. METHODS: This prospective case series included consecutive adult patients with findings of transverse maxillary deficiency that underwent the 2PENN procedure from 4/2021 to 4/2022. Patients completed pre- and post-operative clinical evaluations, Nasal Obstruction and Septoplasty Effectiveness (NOSE) questionnaires, and computed tomography (CT), with measures including expansion at the level of the posterior nasal spine (PNS), first maxillary inter-molar distance (IMD), and anterior nasal spine (ANS). RESULTS: The cohort (N = 20) was middle-aged (39 ± 11 years), predominantly male (80%), and overweight (BMI 28 ± 4 kg/m2 ). The majority (85%) of patients had sleep breathing issues, of which 10 (59%) had polysomnography-confirmed obstructive sleep apnea (OSA). Full anterior-posterior separation of the mid-palatal suture line was evident on all post-operative CT scans, with mean expansion at the PNS of 3.6 ± 1.3 mm, IMD of 6.1 ± 1.6 mm and ANS of 7.0 ± 1.6 mm (p < 0.001). Following surgery, mean NOSE scores improved from 57 ± 23 to 14 ± 13 (p < 0.001). One patient required maxillary antrostomy for post-operative sinusitis. CONCLUSION: 2PENN is an effective and safe technique for achieving both anterior and posterior maxillary expansion in patients with transverse maxillary deficiency. Further study is warranted to better understand the effect of 2PENN in patients with OSA, particularly as it relates to improving pharyngeal patency. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:1970-1977, 2024.

The Implant-borne Articulation Splint in Fibula Free Flap Mandibular Reconstruction: A Technical Note.

Computer-aided design and computer-aided manufacturing and digitally simulated surgeries have revolutionized maxillomandibular reconstruction. In particular, this technology has increased the accuracy and facilitated the process of dental implantation in fibula free flaps. Despite the efficacy of virtual planning, there is a minor degree of translational difference between digital and intraoperative measurements, which may affect the precision of implant and fibula orientations. This is especially concerning during the last stage of fibula insetting, where the graft segments have the potential to roll, yaw, or pitch. The objective of this study is to describe an advanced prosthodontic technique that ensures the fibula grafts and implants remain in a restorable position during final insetting. We describe the technique and workflow of the implant-borne articulation splint through a case presentation and demonstrate results at 4 months postoperative and postradiotherapy. Given the degree of investment placed in virtual planning, free flap reconstruction, and endosteal implants, a technique that ensures optimal restorability of each implant is pivotal. Larger studies are still required to fully elucidate the cost-effectiveness and long-term results of the implant-borne articulation splint.

Coordination between aminoacylation and editing to protect against proteotoxicity.

Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that ligate amino acids to tRNAs, and often require editing to ensure accurate protein synthesis. Recessive mutations in aaRSs cause various neurological disorders in humans, yet the underlying mechanism remains poorly understood. Pathogenic aaRS mutations frequently cause protein destabilization and aminoacylation deficiency. In this study, we report that combined aminoacylation and editing defects cause severe proteotoxicity. We show that the ths1-C268A mutation in yeast threonyl-tRNA synthetase (ThrRS) abolishes editing and causes heat sensitivity. Surprisingly, experimental evolution of the mutant results in intragenic mutations that restore heat resistance but not editing. ths1-C268A destabilizes ThrRS and decreases overall Thr-tRNAThr synthesis, while the suppressor mutations in the evolved strains improve aminoacylation. We further show that deficiency in either ThrRS aminoacylation or editing is insufficient to cause heat sensitivity, and that ths1-C268A impairs ribosome-associated quality control. Our results suggest that aminoacylation deficiency predisposes cells to proteotoxic stress.

Analysis of postoperative complications related to cannabis and tobacco usage in patients undergoing mandible facial fracture surgeries.

BACKGROUND: Cannabis is the third most used controlled substance in the world. Despite its widespread use, minimal research investigates cannabis usage in patients undergoing facial fracture surgeries. This study aimed to evaluate patterns of postoperative complications related to cannabis and tobacco usage after mandible fracture surgeries. MATERIALS AND METHODS: PearlDiver™, a commercially available healthcare database, was used to identify patients endorsing the use of cannabis, tobacco, or both who underwent mandible fracture surgeries for cross-sectional analysis. The study population was categorized into groups using the Classification of Diseases, 9th revision (ICD-9), ICD-10, and Current Procedural Terminology (CPT) codes. A chi-square analysis was performed to assess the influence of cannabis and tobacco use on postoperative complications. RESULTS: A total of 8288 patients met the inclusion criteria, with 72 patients with cannabis-only usage, 914 patients with cannabis and tobacco usage, 3236 patients with tobacco-only usage, and 4066 in the control group. For patients using only cannabis, there was not an increased risk of developing postoperative complications compared with the control population. Patients with concurrent cannabis and tobacco usage and those with tobacco-only usage had an increased risk of surgical site infection, facial nonunion, facial abscess, debridement, and malocclusion after surgical repair of mandibular facial fracture. CONCLUSION: Patients with tobacco-only as well as cannabis and tobacco usage had an increased risk of all postoperative complications, except malocclusion, compared with cannabis-only. Based on the results of this study, it is recommended that healthcare providers consider a patient's history of tobacco use when planning and performing surgical treatment for traumatic mandible fractures.

TURBOMOLE: Today and Tomorrow.

TURBOMOLE is a highly optimized software suite for large-scale quantum-chemical and materials science simulations of molecules, clusters, extended systems, and periodic solids. TURBOMOLE uses Gaussian basis sets and has been designed with robust and fast quantum-chemical applications in mind, ranging from homogeneous and heterogeneous catalysis to inorganic and organic chemistry and various types of spectroscopy, light-matter interactions, and biochemistry. This Perspective briefly surveys TURBOMOLE's functionality and highlights recent developments that have taken place between 2020 and 2023, comprising new electronic structure methods for molecules and solids, previously unavailable molecular properties, embedding, and molecular dynamics approaches. Select features under development are reviewed to illustrate the continuous growth of the program suite, including nuclear electronic orbital methods, Hartree-Fock-based adiabatic connection models, simplified time-dependent density functional theory, relativistic effects and magnetic properties, and multiscale modeling of optical properties.

Updates in Traumatic Lower Extremity Free Flap Reconstruction.

SUMMARY: Lower extremity reconstruction, particularly in the setting of trauma, remains one of the most challenging tasks for the plastic surgeon. Advances in wound management and microsurgical techniques in conjunction with long-term outcomes studies have expanded possibilities for limb salvage, but many aspects of management have continued to rely on principles set forth by Gustilo and Godina in the 1980s. The purpose of this article is to provide a comprehensive update on the various management aspects of traumatic lower extremity microvascular reconstruction based on the latest evidence, with an examination of recent publications.

Hypoglossal Nerve Stimulator Explantation Technique and Outcomes: A Retrospective Case Series.

INTRODUCTION: Upper airway stimulation via the hypoglossal nerve stimulator (HGNS) implant is a surgical method for treating obstructive sleep apnea. However, patients may need the implant removed for a variety of reasons. The purpose of this case series is to assess surgical experiences with HGNS explantation at our institution. We report on surgical approach, overall operative times, operative and postoperative complications, and discuss relevant patient-specific surgical findings when removing the HGNS. METHODS: We performed a retrospective case series of all patients that underwent HGNS implantation at a single tertiary medical center between January 9, 2021, and January 9, 2022. Subjects included adult patients who presented to the sleep surgery clinic of the senior author for surgical management of previously implanted HGNS. Patient clinical history was reviewed to determine the timing of the patient's implant, reasons for explant, and postoperative recovery course. Operative reports were reviewed to determine overall duration of surgery and any associated difficulties or deviations from the general approach. RESULTS: Between January 9, 2021, and January 9, 2022, 5 patients had an explantation of their HGNS implant. Explantation occurred between 8 and 63 months of their original implant surgery. The average operative time from incisional start time to close was 162 min for all cases with a range of 96-345 min. No significant complications were reported including pneumothorax and nerve palsy. CONCLUSION: This reported case series outlines the general steps for Inspire HGNS explantation as well as details the experiences in a case series of 5 subjects explanted over the year at a single institution. The results from the cases suggest that the explantation of the device can be performed efficiently and safely.

Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan.

Metabolism is deeply intertwined with aging. Effects of metabolic interventions on aging have been explained with intracellular metabolism, growth control, and signaling. Studying chronological aging in yeast, we reveal a so far overlooked metabolic property that influences aging via the exchange of metabolites. We observed that metabolites exported by young cells are re-imported by chronologically aging cells, resulting in cross-generational metabolic interactions. Then, we used self-establishing metabolically cooperating communities (SeMeCo) as a tool to increase metabolite exchange and observed significant lifespan extensions. The longevity of the SeMeCo was attributable to metabolic reconfigurations in methionine consumer cells. These obtained a more glycolytic metabolism and increased the export of protective metabolites that in turn extended the lifespan of cells that supplied them with methionine. Our results establish metabolite exchange interactions as a determinant of cellular aging and show that metabolically cooperating cells can shape the metabolic environment to extend their lifespan.

Room-Temperature Stable Ln(II) Complexes Supported by 2,6-Diadamantyl Aryloxide Ligands.

The sterically bulky aryloxide ligand OAr* (OAr* = -OC6H2-Ad2-2,6tBu-4; Ad = 1-adamantyl) has been used to generate Ln(II) complexes across the lanthanide series that are more thermally stable than complexes of any other ligand system reported to date for 4fnd1 Ln(II) ions. The Ln(III) precursors Ln(OAr*)3 (1-Ln) were synthesized by reacting 1.2 equiv of Ln(NR2)3 (R = SiMe3) with 3 equiv of HOAr* for Ln = La, Ce, Nd, Gd, Dy, Yb, and Lu. 1-Ce, 1-Nd, 1-Gd, 1-Dy, and 1-Lu were identified by single-crystal X-ray diffraction studies. Reductions of 1-Ln with potassium graphite (KC8) in tetrahydrofuran in the presence of 2.2.2-cryptand (crypt) yielded the Ln(II) complexes [K(crypt)][Ln(OAr*)3] (2-Ln). The 2-Ln complexes for Ln = Nd, Gd, Dy, and Lu were characterized by X-ray crystallography and found to have Ln-O bond distances 0.038-0.087 Å longer than those of their 1-Ln analogues; this is consistent with 4fn5d1 electron configurations. The structure of 2-Yb has Yb-O distances 0.167 Å longer than those predicted for 1-Yb, which is consistent with a 4f14 electron configuration. Although 2-La and 2-Ce proved to be challenging to isolate, with 18-crown-6 (18-c-6) as the potassium chelator, La(II) and Ce(II) complexes with OAr* could be isolated and crystallographically characterized: [K(18-c-6)][Ln(OAr*)3] (3-Ln). The Ln(II) complexes decompose at room temperature more slowly than other previously reported 4fn5d1 Ln(II) complexes. For example, only 30% decomposition of 2-Dy was observed after 30 h at room temperature compared to complete decomposition of [Dy(OAr')3]- and [DyCp'3]- under similar conditions (OAr' = OC6H2-2,6-tBu2-4-Me; Cp' = C5H4SiMe3).

Exploratory Study on the Clinical use of EEG for the People with Chronic Stroke and Their Correlation with the Neuropsychological Outcome.

Objective. To measure the EEG signals of the people with chronic stroke in eyes-closed and eyes-open condition and study their relationship with the cognitive function and mental wellbeing. Methods. The investigators would conduct cognitive and mental wellbeing tests on recruited subjects. Their EEG signal was acquired by the 16-channel EEG system. The absolute power under different frequency bands and EEG indices (delta alpha ratio and pairwise derived brain symmetry index) in different eye conditions was calculated. Pearson's correlation was conducted to investigate the association between the clinical tests and the EEG index. Results. 32 subjects were recruited for the study. There was a significant correlation between the pairwise derived brain symmetry index (pdBSI) in eyes-open condition with the Stroop Test (p = .002), Paced Auditory Serial Addition Test-3 s (p = .008)/2 s (p = .002) and WHO-5 well-being scale (p = .023). Conclusions. There is a significant correlation between the brain symmetry index and the cognitive and wellbeing assessment. Brain symmetry index over the delta frequency has been found to be the most useful parameter relating to the clinical score.Significance:It is recommended to use EEG as an adjunctive neuropsychological assessment in clinics for people with chronic stroke, especially for clients who could not undertake conventional assessments (eg aphasia, attention problem).Highlights: There is a significant correlation between the EEG index and the clinical neuropsychological assessmentPairwise Derived Brain Symmetry index in delta frequency range correlated with most of the neuropsychological outcome.It is feasible for us to adopt EEG as an adjunctive assessment in clinical settings.

Outcomes and Perioperative Risk Factors after Oncologic Free-Flap Scalp Reconstruction.

BACKGROUND: Little is known about the risk factors associated with complications after free flap scalp reconstruction. The purpose of this study was to identify patient, scalp defect, and flap characteristics associated with increased risk of surgical complications. METHODS: A retrospective study was performed of free-flap scalp reconstruction in oncologic patients at Memorial Sloan Kettering Cancer Center from 2002 to 2017. Data collection included patient, defect, flap, and complication characteristics. Complications were classified into major, defined as complications requiring surgical intervention, and minor, defined as complications requiring conservative treatment. Risk factors and outcome variables were compared using chi-square with Fisher's exact test. RESULTS: A total of 63 free flaps to the scalp in 58 patients were performed; average follow-up was 3.5 years. Most flaps were muscle-only or musculocutaneous. One-third of patients with free flaps experienced complications (n = 21, 15 major and 6 minor). Examining risk factors for complications, patients with cardiovascular disease were nearly three times more likely to have suffered a major complication than patients without cardiovascular disease (36.7 vs. 12.1%, p = 0.04). This was the only significant risk factor noted. Perioperative radiotherapy, prior scalp surgery, flap type, and recipient vessel selection were found to be nonsignificant risk factors. CONCLUSION: Cardiovascular disease may be a significant marker of risk for major complications in patients undergoing free-flap reconstruction of the scalp. This information should be used to help guide perioperative counseling and decision making in this challenging patient population.

The Accuracy and Reliability of Visually Assessed Pharyngeal Opening Pressures During Drug-Induced Sleep Endoscopy.

OBJECTIVE: To examine the accuracy and interrater reliability of a visually assessed vs airflow-based measure of pharyngeal collapsibility obtained in patients with obstructive sleep apnea undergoing drug-induced sleep endoscopy (DISE). STUDY DESIGN: Prospective observational study. SETTING: Academic tertiary care practice. METHODS: Patients underwent DISE with airflow monitoring and nasal positive airway pressure titration to determine visual and airflow-based levels of pharyngeal opening pressure (PhOP). Visual DISE-PhOP was assessed by 2 blinded independent raters and defined as the pressure at which visual confirmation of airway collapse, including snoring, was abolished. Airflow-based DISE-PhOP was defined as the minimally effective positive airway pressure that abolished inspiratory flow limitation. Equivalence testing between visual and airflow DISE-PhOP of each rater was performed with the two one sided T-test (TOST) with an a priori equivalence bound of ±1 cm H2 O. Interrater reliability was evaluated with the intraclass correlation coefficient. RESULTS: One hundred patients were enrolled in the study and 77 completed the full evaluation. The population was predominantly male (74%) with an average age of 54.8 years, body mass index of 30.1 kg/m2 , and apnea-hypopnea index of 30.7 events/h. Equivalence testing showed that both raters were within ±1 cm H2 O of airflow-based DISE-PhOP (-0.43 to 0.09 cm H2 O and -0.32 to 0.48 cm H2 O). Interrater reliability of visual DISE-PhOP between the raters was also good to excellent with an intraclass correlation coefficient of 0.895 (95% CI, 0.84-0.932). CONCLUSION: DISE-PhOP, a measure of upper airway collapsibility, was equivalent between airflow-based and visual assessments with strong interrater reliability, supporting its adoption as a standardized objective parameter in clinical DISE.

Inorganic sulfur fixation via a new homocysteine synthase allows yeast cells to cooperatively compensate for methionine auxotrophy.

The assimilation, incorporation, and metabolism of sulfur is a fundamental process across all domains of life, yet how cells deal with varying sulfur availability is not well understood. We studied an unresolved conundrum of sulfur fixation in yeast, in which organosulfur auxotrophy caused by deletion of the homocysteine synthase Met17p is overcome when cells are inoculated at high cell density. In combining the use of self-establishing metabolically cooperating (SeMeCo) communities with proteomic, genetic, and biochemical approaches, we discovered an uncharacterized gene product YLL058Wp, herein named Hydrogen Sulfide Utilizing-1 (HSU1). Hsu1p acts as a homocysteine synthase and allows the cells to substitute for Met17p by reassimilating hydrosulfide ions leaked from met17Δ cells into O-acetyl-homoserine and forming homocysteine. Our results show that cells can cooperate to achieve sulfur fixation, indicating that the collective properties of microbial communities facilitate their basic metabolic capacity to overcome sulfur limitation.

Lentiviral Gene Therapy for Artemis-Deficient SCID.

BACKGROUND: The DNA-repair enzyme Artemis is essential for rearrangement of T- and B-cell receptors. Mutations in DCLRE1C, which encodes Artemis, cause Artemis-deficient severe combined immunodeficiency (ART-SCID), which is poorly responsive to allogeneic hematopoietic-cell transplantation. METHODS: We carried out a phase 1-2 clinical study of the transfusion of autologous CD34+ cells, transfected with a lentiviral vector containing DCLRE1C, in 10 infants with newly diagnosed ART-SCID. We followed them for a median of 31.2 months. RESULTS: Marrow harvest, busulfan conditioning, and lentiviral-transduced CD34+ cell infusion produced the expected grade 3 or 4 adverse events. All the procedures met prespecified criteria for feasibility at 42 days after infusion. Gene-marked T cells were detected at 6 to 16 weeks after infusion in all the patients. Five of 6 patients who were followed for at least 24 months had T-cell immune reconstitution at a median of 12 months. The diversity of T-cell receptor ß chains normalized by 6 to 12 months. Four patients who were followed for at least 24 months had sufficient B-cell numbers, IgM concentration, or IgM isohemagglutinin titers to permit discontinuation of IgG infusions. Three of these 4 patients had normal immunization responses, and the fourth has started immunizations. Vector insertion sites showed no evidence of clonal expansion. One patient who presented with cytomegalovirus infection received a second infusion of gene-corrected cells to achieve T-cell immunity sufficient for viral clearance. Autoimmune hemolytic anemia developed in 4 patients 4 to 11 months after infusion; this condition resolved after reconstitution of T-cell immunity. All 10 patients were healthy at the time of this report. CONCLUSIONS: Infusion of lentiviral gene-corrected autologous CD34+ cells, preceded by pharmacologically targeted low-exposure busulfan, in infants with newly diagnosed ART-SCID resulted in genetically corrected and functional T and B cells. (Funded by the California Institute for Regenerative Medicine and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT03538899.).