IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat.

While mechanisms controlling uncoupling protein-1 (UCP1) in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis, it remains unclear whether F1Fo-ATP synthase function is also regulated in brown adipose tissue (BAT). Here, we show that inhibitory factor 1 (IF1, encoded by Atp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In vivo, IF1 levels are diminished in BAT of cold-adapted mice compared to controls. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential (MMP) through ATP hydrolysis (the so-called "reverse mode" of ATP synthase) is increased in brown fat. In cultured brown adipocytes, IF1 overexpression results in an inability of mitochondria to sustain the MMP upon adrenergic stimulation, leading to a quiescent-like phenotype in brown adipocytes. In mice, adeno-associated virus-mediated IF1 overexpression in BAT suppresses adrenergic-stimulated thermogenesis and decreases mitochondrial respiration in BAT. Taken together, our work identifies downregulation of IF1 upon cold as a critical event for the facilitation of the reverse mode of ATP synthase as well as to enable energetic adaptation of BAT to effectively support non-shivering thermogenesis.

Multi-locus sequence typing and phylogenetics of Cryptococcus neoformans AD hybrids.

Hybrid AD strains of the human pathogenic Cryptococcus neoformans species complex have been reported from many parts of the world. However, their origin, diversity, and evolution are incompletely understood. In this study, we analyzed 102 AD hybrid strains representing 21 countries on five continents. For each strain, we obtained its mating type and its allelic sequences at each of the seven loci that have been used for genotyping haploid serotypes A and D strains of the species complex by the Cryptococcus research community. Our results showed that most AD hybrids exhibited loss of heterozygosity at one or more of the seven analyzed loci. Phylogenetic and population genetic analyses of the allelic sequences revealed multiple origins of the hybrids within each continent, dating back to one million years ago in Africa and up to the present in other continents. We found evidence for clonal reproduction and long-distance dispersal of these hybrids in nature. Comparisons with the global haploid serotypes A and D strains identified new alleles and new haploid multi-locus genotypes in AD hybrids, consistent with the presence of yet-to-be discovered genetic diversity in haploid populations of this species complex in nature. Together, our results indicate that AD hybrids can be effectively genotyped using the same multi-locus sequencing type approach as that established for serotypes A and D strains. Our comparisons of the AD hybrids among each other as well as with the global haploid serotypes A and D strains revealed novel genetic diversity as well as evidence for multiple origins and dynamic evolution of these hybrids in nature.

NEK10 kinase ablation affects mitochondrial morphology, function and protein phosphorylation status.

BACKGROUND: NEK10, a serine/threonine/tyrosine kinase belonging to the NEK (NIMA-related kinases) family, has been associated with diverse cellular processes. However, no specific target pathways have been identified. Our previous work knocking down NEK10 in HeLa cells suggested a functional association with mitochondria, as we observed altered mitochondrial morphology, mitochondrial oxygen consumption, mtDNA integrity, and reactive oxygen species levels. METHODS: To better understand this association, we studied human HAP1 cells fully knockout for NEK10 and confirmed that NEK10 has an important role in mitochondrial homeostasis. We performed the study of mitochondrial respiration, mitochondrial morphology, mitochondrial mass, and mtDNA analysis. Additionally, we showed proteome and phosphoproteome data of crude mitochondrial fraction of Parental and NEK10 KO cells using liquid chromatography-mass spectrometry (LC-MS/MS). RESULTS: In the absence of NEK10 several mitochondrial functions were disturbed. Moreover, proteome and phosphoproteome analyses of mitochondrial fractions showed that NEK10 alters the threonine phosphorylation status of several mitochondrial/endoplasmic reticulum components, including HSP60, NDUFB4, and TOM20. These changes impacted the steady-state levels of a larger group of proteins, preferentially involving respiratory complexes and autophagy pathways. CONCLUSION: We concluded that NEK10 plays a key role in mitochondrial function, possibly by modulating the phosphorylation status of mitochondrial proteins.

Scaptona ramosa gen. nov., sp. nov., isolated from nest of the stingless bee.

In this study, a novel genus is proposed, Scaptona, with a novel species, Scaptona ramosa, isolated from nests of stingless bees (Scaptotrigona sp.). The taxonomic novelty was determined by the phylogenetic analysis of DNA sequences from the internal transcribed spacer regions, small subunit rRNA (18S rRNA), large subunit rRNA (28S rRNA) and the RNA polymerase II second-largest subunit gene (RPB2) and paired with our morphological studies. Based on this single species, Scaptona is characterized by greyish green to dark grey colonies, densely and profusely branched conidiophores and single-celled, variously shaped hyaline conidia. Scaptona ramosa constitutes a distinct, well-supported lineage within Cephalothecaceae and can be clearly distinguished from other genera both by DNA sequence analysis and morphological traits. The holotype of S. ramosa is URM 95352. The ex-type strain has been deposited in the Micoteca URM culture collection as URM 8721T and URM 8722. The MycoBank accession number is MB 849456 for the genus and MB 849456 for the species.

Elevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone.

Adjunctive treatment with antiinflammatory corticosteroids like dexamethasone increases survival in tuberculosis meningitis. Dexamethasone responsiveness associates with a C/T variant in Leukotriene A4 Hydrolase (LTA4H), which regulates expression of the proinflammatory mediator leukotriene B4 (LTB4). TT homozygotes, with increased expression of LTA4H, have the highest survival when treated with dexamethasone and the lowest survival without. While the T allele is present in only a minority of the world's population, corticosteroids confer modest survival benefit worldwide. Using Bayesian methods, we examined how pretreatment levels of cerebrospinal fluid proinflammatory cytokines affect survival in dexamethasone-treated tuberculous meningitis. LTA4H TT homozygosity was associated with global cytokine increases, including tumor necrosis factor. Association between higher cytokine levels and survival extended to non-TT patients, suggesting that other genetic variants may also induce dexamethasone-responsive pathological inflammation. These findings warrant studies that tailor dexamethasone therapy to pretreatment cerebrospinal fluid cytokine concentrations, while searching for additional genetic loci shaping the inflammatory milieu.

Hindfoot Alignment in Pediatrics: The Relationship Between Hindfoot Moment Arm and Hindfoot Alignment Angle.

BACKGROUND: Various measurements are used to evaluate hindfoot alignment and determine appropriate treatment, though the best tool is not known. Few studies have examined the relationship between these measurements in pediatric patients. This study sought to compare Hindfoot Moment Arm (HMA) and Hindfoot Alignment Angle (HAA) in evaluation of pediatric hindfoot deformity. METHODS: This was a retrospective cohort study of pediatric patients by age: school-aged (7 to 10 years old), preadolescents (11 to 14), and adolescents (15 to 18). A total of 10 males and 10 females were randomly selected for each cohort from patients with available hindfoot radiographs. HMA and HAA were measured by 2 independent reviewers. Pearson correlation of HMA and HAA was performed by age cohort. Multivariable linear regression was used to investigate the association of HMA and HAA adjusting for age, sex, height, and weight. RESULTS: Sixty participants were analyzed. Interrater reliability was found to be excellent for HMA and HAA (ICC=0.996 and 0.992, respectively). HMA was 8.7±9.4 mm in school age, 5.7±6.7 mm in preadolescents, and 2.5±13.0 mm among adolescents (P=0.153). HAA was 6.3±9.7 degrees in school age, 6.7±8.6 degrees in preadolescents, and 6.0±14.5 degrees among adolescents (P=0.983). The Pearson correlation coefficient was 0.78 (CI: 0.51-0.91) for school-aged, 0.92 (CI: 0.81-0.97) for preadolescents, and 0.86 (CI: 0.67-0.94) for adolescents. Using multivariable regression, each degree increase in HAA, increased HMA by 0.77 mm. Age, height, and weight were not found to be independent predictors of HMA. CONCLUSIONS: HMA and HAA were both found to be reliable measurements across all age cohorts. When comparing across age cohorts, neither HMA nor HAA differed significantly (P=0.153 and 0.983, respectively). Furthermore, Pearson correlation demonstrated a linear relationship between HMA and HAA. When evaluating hindfoot deformity, surgeons may assess hindfoot alignment via either HMA or HAA regardless of patient age. The authors support the use of HMA for clinical and academic purposes as HMA is considerably simpler to measure. LEVEL OF EVIDENCE: Level III.

Hemiepiphysiodesis for Genu Valgum in Patients With Multiple Hereditary Exostoses.

BACKGROUND: Genu valgum is a well-known feature of multiple hereditary exostoses (MHE). Though prior reports have demonstrated successful treatment with hemiepiphysiodesis, details regarding the correction rate and comparison to an idiopathic population are lacking. This study aimed to detail our institution's experience with guided growth of the knee in patients with MHE and compare this to an idiopathic population. METHODS: All pediatric patients (age 18 and younger) with MHE who underwent lower extremity hemiepiphysiodesis at a tertiary care medical center between January 2016 and December 2022 were retrospectively reviewed. Preoperative and postoperative mechanical lateral distal femoral angle (mLDFA) and medial proximal tibial angle (MPTA, the primary outcomes) were measured in addition to mechanical axis deviation (MAD) and hip-knee-ankle angle (HKA). Patients were 1:2 matched based on age, sex, and physes instrumented to a cohort with idiopathic genu valgum. RESULTS: A total of 21 extremities in 16 patients with MHE underwent hemiepiphysiodesis of the distal femur, proximal tibia, and/or distal tibia. The mean age at surgery was 11.7±2.2 years. Mean MAD corrected from zone 1.9±0.7 to -0.3±1.5, while mLDFA corrected from 83.4±2.9 to 91.7±5.2 degrees and MPTA corrected from 95.3±3.6 to 90.5±4.0 degrees in distal femurs and proximal tibias undergoing guided growth, respectively. Three extremities (14.3%) experienced overcorrection ≥5 degrees managed with observation. There were no differences in correction rates per month for mLDFA (0.54±0.34 vs. 0.51±0.29 degrees, P =0.738) or MPTA (0.31±0.26 vs. 0.50±0.59 degrees, P =0.453) between MHE and idiopathic groups. For 11 extremities in the MHE group with open physes at hardware removal, they experienced a mean recurrence of HKA of 4.0±3.4 degrees at 19-month follow-up. CONCLUSION: Hemiepiphysiodesis corrects lower extremity malalignment in patients with MHE at a similar rate compared with an idiopathic coronal plane deformity population. Rebound deformity of 4 degrees at 19 months after hardware removal in patients with remaining open growth plates should make surgeons conscious of the remaining growth potential when planning deformity correction. LEVEL OF EVIDENCE: Level III.

Novel Surface Topographic Assessment of Lung Volume and Pulmonary Function Tests in Idiopathic Scoliosis: A Preliminary Study.

OBJECTIVE: Severe spinal deformity results in restrictive pulmonary disease from thoracic distortions and lung-volume limitations. Though spirometry and body plethysmography are widely accepted tests for pulmonary function tests (PFTs), they are time-consuming and require patient compliance. This study investigates whether surface topographic [surface topography (ST)] measurements of body volume difference (BVD) and torso volume difference between maximum inhale and exhale correlate to values determined on PFTs. METHODS: This study included patients with idiopathic scoliosis and thoracic/thoracolumbar curves ≥40 degrees. Patients received ST scans, clinical examinations, and EOS biplanar radiographs on the same day. PFTs were performed within 3 months of ST/radiographic analysis. Univariate linear regression analysis was used to examine relationships between BVD, PFT values, and mean curves. RESULTS: Sixteen patients (14.6 ± 2.2 y, 69% females) with idiopathic scoliosis and mean thoracic/thoracolumbar curves of 62 degrees ± 15˚ degrees (45 degrees to 93 degrees) were assessed. BVD displayed statistically high-positive positive correlations with forced vital capacity ( R = 0.863, P < 0.0001), forced expiratory volume in 1 second ( R = 0.870, P < 0.001), vital capacity ( R = 0.802, P < 0.0001), and TLC ( R = 0.831, P < 0.0001. Torso volume difference showed similarly high positive correlations to forced vital capacity, forced expiratory volume in 1 second, vital capacity, and TLC, but not residual volume. No correlations emerged between the mean thoracic/thoracolumbar curve and BVD or PFT values. CONCLUSION: This study strongly endorses further investigation into ST scanning as an alternative to traditional PFTs for assessing pulmonary volumes. The noncontact and noninvasive nature of ST scanning presents a valuable alternative method for analyzing thoracic volume, particularly beneficial for patients unable to cooperate with standard PFTs. LEVEL OF EVIDENCE: Level II-prognostic.

Utilizing robotic-assisted navigation for pelvic instrumentation in pediatric patients with neuromuscular scoliosis: a technical note and case series.

Pelvic fixation is commonly used in correcting pelvic obliquity in pediatric patients with neuromuscular scoliosis and in preserving stability in adult patients with lumbosacral spondylolisthesis or instances of traumatic or osteoporotic fracture. S2-alar-iliac screws are commonly used in this role and have been proposed to reduce implant prominence when compared to traditional pelvic fusion utilizing iliac screws. The aim of this technical note is to describe a technique for robotically navigated placement of S2-alar-iliac screws in pediatric patients with neuromuscular scoliosis, which (a) minimizes the significant exposure needed to identify a bony start point, (b) aids in instrumenting the irregular anatomy often found in patients with neuromuscular scoliosis, and (c) allows for greater precision than traditional open or fluoroscopic techniques. We present five cases that underwent posterior spinal fusion to the pelvis with this technique that demonstrate the safety and efficacy of this procedure.

Practices and Outcomes from a Prospective, Multicenter Registry for Preterm Newborns with Pulmonary Hypertension.

OBJECTIVE: To describe current treatment practices of preterm infants with early hypoxemic respiratory failure (HRF) and pulmonary hypertension (PH) and their association with patient outcomes. STUDY DESIGN: We developed a prospective, observational, multicenter clinical registry of preterm newborns <34 weeks' gestation with HRF and PH, based on either clinical or echocardiographic evidence during the first 72 hours of life, from 28 neonatal intensive care units in the US from 2017 through 2022. The primary end point was mortality among those who did or did not receive PH-targeted treatment, and the secondary end points included comparisons of major morbidities. Variables were compared using t tests, Wilcoxon rank-sum tests, Fisher exact tests, and χ² tests. RESULTS: We analyzed the results of 224 preterm infants enrolled in the registry. Of which, 84% (188/224) received PH-targeted treatment, most commonly inhaled nitric oxide (iNO). Early mortality in this cohort was high, as 33% (71/224) of this sample died in the first month of life, and 77% of survivors (105/137) developed bronchopulmonary dysplasia. Infants who received PH-targeted treatment had higher oxygenation indices at the time of enrollment (28.16 [IQR: 13.94, 42.5] vs 15.46 [IQR: 11.94, 26.15]; P = .0064). Patient outcomes did not differ between those who did or did not receive PH-targeted therapy. CONCLUSIONS: Early-onset HRF with PH in preterm infants is associated with a high early mortality and a high risk of developing bronchopulmonary dysplasia. iNO is commonly used to treat early-onset PH in preterm infants with HRF. In comparison with untreated infants with lower oxygenation indices, iNO treatment in severe PH may prevent poorer outcomes.

Prognostic Significance and Management of Sentinel Nodes in the Triangular Intermuscular Space of Patients with Melanoma.

BACKGROUND: The clinical significance of sentinel nodes (SNs) in the triangular intermuscular space (TIS) of patients with melanoma is poorly understood. This study aimed to determine their incidence and positivity rate, and to report their management and patient outcomes. METHODS: This was a single-institution retrospective cohort study of patients with unilateral or bilateral TIS SNs on lymphoscintigraphy treated between 1992 and 2017. Recurrence-free survival was analyzed. RESULTS: Lymphoscintigraphy identified TIS SNs in 266 patients. They were bilateral in 17 patients. Of the 2296 patients with a melanoma on the upper back, 259 (11%) had TIS SNs. Procurement of SNs was not attempted in 122 (43%) of the 283 cases and failed in 11 cases (7%). An SN was successfully retrieved from the TIS in 145 patients (53%) and contained metastasis in 18 of 150 TIS SNs. This was the only positive SN in 12 patients (8%), upstaging all of them. Of the 18 patients with a positive SN in the TIS, 9 (50%) underwent completion axillary lymph node dissection, but no additional involved nodes were found in any of these patients. Recurrence in the TIS was observed in six patients (5%), none of whom had their TIS SN surgically pursued previously. CONCLUSIONS: Lymphoscintigraphy showed TIS SNs in 11% of patients with melanomas on their upper back. In such cases, retrieval of TIS SNs is required for accurate staging and to minimize the risk of TIS recurrence.

Calculating Multidimensional Optical Spectra from Classical Trajectories.

Multidimensional optical spectra are measured from the response of a material system to a sequence of laser pulses and have the capacity to elucidate specific molecular interactions and dynamics whose influences are absent or obscured in a conventional linear absorption spectrum. Interpretation of complex spectra is supported by theoretical modeling of the spectroscopic observable, requiring implementation of quantum dynamics for coupled electrons and nuclei. Performing numerically correct quantum dynamics in this context may pose computational challenges, particularly in the condensed phase. Semiclassical methods based on calculating classical trajectories offer a practical alternative. Here I review the recent application of some semiclassical, trajectory-based methods to nonlinear molecular vibrational and electronic spectra.

Advances in robotics and pediatric spine surgery.

PURPOSE OF REVIEW: Robotic-assisted surgical navigation for placement of pedicle screws is one of the most recent technological advancements in spine surgery. Excellent accuracy and reliability results have been documented in the adult population, but adoption of robotic surgical navigation is uncommon in pediatric spinal deformity surgery. Pediatric spinal anatomy and the specific pediatric pathologies present unique challenges to adoption of robotic assisted spinal deformity workflows. The purpose of this article is to review the safety, accuracy and learning curve data for pediatric robotic-assisted surgical navigation as well as to identify "best use" cases and technical tips. RECENT FINDINGS: Robotic navigation has been demonstrated as a safe, accurate and reliable method to place pedicle screws in pediatric patients with a moderate learning curve. There are no prospective studies comparing robotically assisted pedicle screw placement with other techniques for screw placement, however several recent studies in the pediatric literature have demonstrated high accuracy and safety as well as high reliability. In addition to placement of pediatric pedicle screws in the thoracic and lumbar spine, successful and safe placement of screws in the pelvis and sacrum have also been reported with reported advantages over other techniques in the setting of high-grade spondylolisthesis as well as pelvic fixation utilizing S2-alar iliac (S2AI) screws. SUMMARY: Early studies have demonstrated that robotically assisted surgical navigation for pedicle screws and pelvic fixation for S2AI screws is safe, accurate, and reliable in the pediatric population with a moderate learning curve.

Success of blinding a procedural intervention in a randomised controlled trial in preterm infants receiving respiratory support.

BACKGROUND: Blinding of treatment allocation from treating clinicians in neonatal randomised controlled trials can minimise performance bias, but its effectiveness is rarely assessed. METHODS: To examine the effectiveness of blinding a procedural intervention from treating clinicians in a multicentre randomised controlled trial of minimally invasive surfactant therapy versus sham treatment in preterm infants of gestation 25-28 weeks with respiratory distress syndrome. The intervention (minimally invasive surfactant therapy or sham) was performed behind a screen within the first 6 h of life by a 'study team' uninvolved in clinical care including decision-making. Procedure duration and the study team's words and actions during the sham treatment mimicked those of the minimally invasive surfactant therapy procedure. Post-intervention, three clinicians completed a questionnaire regarding perceived group allocation, with the responses matched against actual intervention and categorised as correct, incorrect, or unsure. Success of blinding was calculated using validated blinding indices applied to the data overall (James index, successful blinding defined as > 0.50), or to the two treatment allocation groups (Bang index, successful blinding: -0.30 to 0.30). Blinding success was measured within staff role, and the associations between blinding success and procedural duration and oxygenation improvement post-procedure were estimated. RESULTS: From 1345 questionnaires in relation to a procedural intervention in 485 participants, responses were categorised as correct in 441 (33%), incorrect in 142 (11%), and unsure in 762 (57%), with similar proportions for each of the response categories in the two treatment arms. The James index indicated successful blinding overall 0.67 (95% confidence interval (CI) 0.65-0.70). The Bang index was 0.28 (95% CI 0.23-0.32) in the minimally invasive surfactant therapy group and 0.17 (95% CI 0.12-0.21) in the sham arm. Neonatologists more frequently guessed the correct intervention (47%) than bedside nurses (36%), neonatal trainees (31%), and other nurses (24%). For the minimally invasive surfactant therapy intervention, the Bang index was linearly related to procedural duration and oxygenation improvement post-procedure. No evidence of such relationships was seen in the sham arm. CONCLUSION: Blinding of a procedural intervention from clinicians is both achievable and measurable in neonatal randomised controlled trials.

Voltage fluctuations and probe frequency jitter in electric force microscopy of a conductor.

Electric force microscopy probes the statistics of electric field fluctuations from a sample surface, both through measurement of the noncontact friction exerted on the oscillating charged probe and by determination of the power spectrum of stochastic probe frequency fluctuations, referred to as "jitter." Here we calculate the frequency jitter power spectrum determined over a conducting sample of finite thickness, whose response is characterized by a dielectric function that is wavevector-dependent. These calculations complement previous predictions of the coefficient of noncontact friction in an electric force microscopy measurement for the same model, and also previous predictions of the jitter power spectrum for a dielectric continuum. The inclusion both of a finite sample thickness and a wavevector-dependent dielectric response can significantly enhance the magnitude of the predicted jitter spectrum for a conductor, relative to a simpler model of an infinitely thick dielectric continuum. These calculations provide a baseline prediction of the jitter power spectrum generated by the dynamics of conduction electrons in a metal sample.

Exploring Correlations Between Pain and Deformity in Idiopathic Scoliosis With Validated Self-reported Pain Scores, Radiographic Measurements, and Trunk Surface Topographic Measurements.

BACKGROUND: Up to 75% of patients with idiopathic scoliosis (IS) report back pain, but the exact contributors are unclear. This study seeks to assess how pain correlates with demographics, radiographic and surface topographic (ST) measurements, and patient-reported outcome measures (PROMs) in patients with IS. METHODS: Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference (PI) and Scoliosis Research Society revised (SRS-22r) pain domain from an IRB approved prospectively collected registry containing patients 11 to 21 years old with IS were correlated (Spearman coefficients) with measurements from whole-body EOS radiography and ST scanning, PROMIS 1.0 PROMs, Trunk Appearance Perception Scale (TAPS), and SRS-22r domains. SRS-22r and PROMIS-PI were also compared between different sex, scoliosis severities, and primary curve locations with Mann-Whitney U or Kruskal-Wallis tests, and if significant differences were found, included with the 5 highest univariate correlated variables into stepwise multivariate linear regression models ( P <0.05 to enter, P >0.1 to remove) predicting SRS-22r pain and PROMIS-PI. RESULTS: One hundred and forty-nine patients (14.5 ± 2.0 y, body mass index 20.6 ± 4.1 kg/m 2 , 96 (64%) female, mean major coronal curve 40 ± 19 deg, range: 10 deg, 83 deg) reported mean PROMIS-PI of 42.2 ± 10.0 and SRS-22r pain of 4.4 ± 0.6. SRS-22r self-image was the most correlated variable with both SRS-22r pain (rho=0.519) and PROMIS-PI (rho=-0.594). Five variables, none of which were ST or radiographic measures, strongly predicted SRS pain domain (R=0.711, R2=0.505, N=138). Two variables (SRS-22r self-image and SRS-22r function) were utilized by a model correlated with PROMIS-PI (R=0.687, R2=0.463, N=124). CONCLUSIONS: SRS-22r function and self-image domains were more strongly correlated with SRS-22r pain and PROMIS-PI than any radiographic or ST measurements. LEVEL OF EVIDENCE: Level II-retrospective study.

Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants: Follow-Up of the OPTIMIST-A Randomized Clinical Trial.

Importance: The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified. Objective: To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years' corrected age. Design, Setting, and Participants: Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years' corrected age was completed on December 9, 2022. Interventions: Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment. Main Outcomes and Measures: The key secondary outcome of death or moderate to severe NDD was assessed at 2 years' corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years. Results: Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, -7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90]). Conclusions and Relevance: In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Enhanced resistance to Ca2+-induced mitochondrial permeability transition in the long-lived red-footed tortoise Chelonoidis carbonaria.

The interaction between supraphysiological cytosolic Ca2+ levels and mitochondrial redox imbalance mediates the mitochondrial permeability transition (MPT). The MPT is involved in cell death, diseases and aging. This study compared the liver mitochondrial Ca2+ retention capacity and oxygen consumption in the long-lived red-footed tortoise (Chelonoidis carbonaria) with those in the rat as a reference standard. Mitochondrial Ca2+ retention capacity, a quantitative measure of MPT sensitivity, was remarkably higher in tortoises than in rats. This difference was minimized in the presence of the MPT inhibitors ADP and cyclosporine A. However, the Ca2+ retention capacities of tortoise and rat liver mitochondria were similar when both MPT inhibitors were present simultaneously. NADH-linked phosphorylating respiration rates of tortoise liver mitochondria represented only 30% of the maximal electron transport system capacity, indicating a limitation imposed by the phosphorylation system. These results suggested underlying differences in putative MPT structural components [e.g. ATP synthase, adenine nucleotide translocase (ANT) and cyclophilin D] between tortoises and rats. Indeed, in tortoise mitochondria, titrations of inhibitors of the oxidative phosphorylation components revealed a higher limitation of ANT. Furthermore, cyclophilin D activity was approximately 70% lower in tortoises than in rats. Investigation of critical properties of mitochondrial redox control that affect MPT demonstrated that tortoise and rat liver mitochondria exhibited similar rates of H2O2 release and glutathione redox status. Overall, our findings suggest that constraints imposed by ANT and cyclophilin D, putative components or regulators of the MPT pore, are associated with the enhanced resistance to Ca2+-induced MPT in tortoises.

Noncontact Friction in Electric Force Microscopy over a Conductor with Nonlocal Dielectric Response.

Electric force microscopy, in which a charged probe moves above a surface, can measure thermally generated electric field fluctuations from the sample. Noncontact friction measurements of energy loss from the probe have been performed over insulators, semiconductors, and conductors and have been interpreted in terms of the dielectric response of the sample. Noncontact friction over metal surfaces has recently been ascribed to dielectric relaxation of adsorbed molecules, motivating the examination of the baseline noncontact friction over a bare metal surface. The noncontact friction for a thin conducting film is calculated for a wavevector-dependent dielectric function, complementing previous calculations for insulators and semiconductors employing a dielectric continuum representation. Inclusion of the wavevector dependence in the dielectric response of a conductor enhances the friction and alters its dependence on tip-sample separation, relative to the continuum treatment.

Two-dimensional vibronic spectroscopy with semiclassical thermofield dynamics.

Thermofield dynamics is an exactly correct formulation of quantum mechanics at finite temperature in which a wavefunction is governed by an effective temperature-dependent quantum Hamiltonian. The optimized mean trajectory (OMT) approximation allows the calculation of spectroscopic response functions from trajectories produced by the classical limit of a mapping Hamiltonian that includes physical nuclear degrees of freedom and other effective degrees of freedom representing discrete vibronic states. Here, we develop a thermofield OMT (TF-OMT) approach in which the OMT procedure is applied to a temperature-dependent classical Hamiltonian determined from the thermofield-transformed quantum mapping Hamiltonian. Initial conditions for bath nuclear degrees of freedom are sampled from a zero-temperature distribution. Calculations of two-dimensional electronic spectra and two-dimensional vibrational-electronic spectra are performed for models that include excitonically coupled electronic states. The TF-OMT calculations agree very closely with the corresponding OMT results, which, in turn, represent well benchmark calculations with the hierarchical equations of motion method.