Systematically missing data in causally interpretable meta-analysis.

Causally interpretable meta-analysis combines information from a collection of randomized controlled trials to estimate treatment effects in a target population in which experimentation may not be possible but from which covariate information can be obtained. In such analyses, a key practical challenge is the presence of systematically missing data when some trials have collected data on one or more baseline covariates, but other trials have not, such that the covariate information is missing for all participants in the latter. In this article, we provide identification results for potential (counterfactual) outcome means and average treatment effects in the target population when covariate data are systematically missing from some of the trials in the meta-analysis. We propose three estimators for the average treatment effect in the target population, examine their asymptotic properties, and show that they have good finite-sample performance in simulation studies. We use the estimators to analyze data from two large lung cancer screening trials and target population data from the National Health and Nutrition Examination Survey (NHANES). To accommodate the complex survey design of the NHANES, we modify the methods to incorporate survey sampling weights and allow for clustering.

Total Syntheses and Absolute Stereochemical Correction of Negundin B, Vitexin 1, and Vitexin 6.

A highly adaptable asymmetric synthetic route toward dihydronaphthalene lignans was developed, with its application to the syntheses of negundin B and vitexin 1/6 described herein. This developed pathway proceeded through an enantioselective aldol reaction to establish the contiguous stereocenters present in the final structures with subsequent functional group transformations yielding (-)-negundin B and (-)-vitexin 1/6. The enantioselective synthesis of vitexin 1/6 allowed the correction of absolute configuration, which has been widely incorrectly reported.

Total Synthesis of (-)-Amovillosumin A and Structure Correction of (-)-Amovillosumin C Using Chemical Synthesis.

Norlignans are a rare class of natural products isolated from a diverse range of plant species, many of which have interesting biological activities including antibacterial, antioxidant, phytotoxic, platelet aggregation inhibitory effects, and more. Isolated from Amomum villosum (Amomi Fructus), amovillosumins A (1) and C (3) are norlignans which were of interest to synthesize, due to their interesting bioactivities, specifically their ability to increase stimulation of glucagon-like peptide-1 (GLP-1) secretion. In this research, key intermediate 15 was used to stereoselectively synthesize (7R,8R)-amovillosumins A (1) and C (3). The developed method includes a Mitsunobu coupling, a modified rhodium-catalyzed Miyaura arylation, and an acid-catalyzed cyclization in key bond-forming steps. After synthesis, the structure of 1 was confirmed, but it was revealed that the benzodioxane-containing structure of amovillosumin C (3) that had been proposed in the literature was incorrect. Thus, with further investigation a structure correction of 3 was achieved by synthesis, the correct structure being 8-O-4'-oxynorlignan.

Total Synthesis of Linear Coumarniolignoids (+) and (-)-Sapiumin C, (-)-Moluccanin, and (-)-Hemidesminine.

Coumarinolignoids (CLs) are a class of natural products isolated from a diverse range of plant species. Due to their unique structural scaffold, they exhibit a wide range of interesting biological activities including hepatoprotective, antitumor, anti-inflammatory, and antioxidant activities among others. In this research, key intermediate 10 was used to stereoselectively synthesize CLs (7'S,8'S)- and (7'R,8'R)-sapiumin C 1 and 2, (7'S,8'S)-moluccanin 3, and (7'S,8'S) hemidesminine 4 for the first time, establishing a versatile synthetic method for the stereoselective synthesis of linear CLs. The developed method includes a Mitsunobu coupling, a modified Miyaura arylation via a rhodium catalyst, and an acid-catalyzed cyclization in key bond-forming steps. The developed synthetic route allows the synthesis of both enantiomers of a given natural product from the same chiral pool reagent (S)-solketal while allowing easy variation of aromatic substitution and hydroxymethyl/allylhydroxymethyl moieties that are common in this class of natural products.

Development of truncated Battacin antimicrobials featuring novel N-terminal fatty acids with an excellent safety profile.

Octapeptin B5 peptides containing a novel fatty acids have been found to have enhanced antibacterial activity against Staphylococcus aureus and also have an excellent safety profile. Cyclic lipopeptides such as the polymyxins and battacin are potent antibacterial agents. It has been shown that truncated, non-linear, versions of these agents (e.g. octapeptin B5) can retain the activity of the more complex cyclic compounds. In this work the synthesis of Octapeptin B5 peptides containing a range of novel fatty acids is reported. Many of these lipopeptides have been found to have enhanced antibacterial activity against Staphylococcus aureus compared to Octapeptin B5 whilst also having an excellent safety profile in haemolytic and cytotoxicity assays.

Synthesis of a novel isotopically labelled standard for quantification of γ-nonalactone in New Zealand Pinot noir via SIDA-SPE-GC-MS.

γ-Nonalactone is a linear aliphatic lactone ubiquitous in wine, associated with coconut, sweet, and stone fruit aroma descriptors. Little research has been conducted looking at the importance of this compound to New Zealand (NZ) wine aroma. 2H213C2-γ-Nonalactone, a novel isotopologue of γ-nonalactone, was synthesised in this work for use in a stable isotope dilution assay (SIDA) for quantification of γ-nonalactone in NZ Pinot noir wines for the first time. Synthesis was carried out using heptaldehyde as the starting material, and 13C atoms and 2H atoms were introduced via Wittig olefination and deuterogenation steps, respectively. The suitability of this compound as an internal standard was demonstrated by spiking model wine at normal and elevated conditions during sample preparation, with subsequent analysis via mass spectrometry showing stability of 2H213C2-γ-nonalactone. A model wine calibration, with concentrations of γ-nonalactone from 0 to 100 µg L-1, was shown to have excellent linearity (R2 > 0.99), reproducibility (0.72%), and repeatability (0.38%). Twelve NZ Pinot noir wines, representative of a range of NZ Pinot noir-producing regions, prices, and vintages, were analysed by solid-phase extraction-gas chromatography-mass spectrometry (SPE-GC-MS). The concentrations of γ-nonalactone ranged from 8.3 to 22.5 µg L-1, the latter of which was close to the odour detection threshold of this compound. These findings provide a basis for further research into γ-nonalactone and its impact on NZ Pinot noir aroma and provide a robust method for the quantification of this compound in Pinot noir.

Safety and Durability of Accelerated Infliximab Dosing Strategies in Pediatric IBD: A Single Center, Retrospective Study.

OBJECTIVES: Infliximab (IFX) is commonly used to treat children with inflammatory bowel disease (IBD). We previously reported that patients with extensive disease started on IFX at a dose of 10 mg/kg had greater treatment durability at year one. The aim of this follow-up study is to assess the long-term safety and durability of this dosing strategy in pediatric IBD. METHODS: We performed a retrospective single-center study of pediatric IBD patients started on IFX over a 10-year period. RESULTS: Two hundred ninety-one patients were included (mean age = 12.61, 38% female) with a follow-up range of 0.1-9.7 years from IFX induction. One hundred fifty-five (53%) were started at a dose of 10 mg/kg. Only 35 patients (12%) discontinued IFX. The median duration of treatment was 2.9 years. Patients with ulcerative colitis ( P ≤ 0.01) and patients with extensive disease ( P = 0.01) had lower durability, despite a higher starting dose of IFX ( P = 0.03). Adverse events (AEs) were observed to occur at a rate of 234 per 1000 patient-years. Patients with a higher serum IFX trough level (≥20 µg/mL) had a higher rate of AEs ( P = 0.01). Use of combination therapy had no impact on risk of AEs ( P = 0.78). CONCLUSIONS: We observed an excellent IFX treatment durability, with only 12% of patients discontinuing therapy over the observed timeframe. The overall rate of AEs was low, the majority being infusion reactions and dermatologic conditions. Higher IFX dose and serum trough level> 20 µg/mL were associated with higher risk of AEs, the majority being mild and not resulting in cessation of therapy.

Addressing Systematic Missing Data in the Context of Causally Interpretable Meta-analysis.

Evidence synthesis involves drawing conclusions from trial samples that may differ from the target population of interest, and there is often heterogeneity among trials in sample characteristics, treatment implementation, study design, and assessment of covariates. Stitching together this patchwork of evidence requires subject-matter knowledge, a clearly defined target population, and guidance on how to weigh evidence from different trials. Transportability analysis has provided formal identifiability conditions required to make unbiased causal inference in the target population. In this manuscript, we review these conditions along with an additional assumption required to address systematic missing data. The identifiability conditions highlight the importance of accounting for differences in treatment effect modifiers between the populations underlying the trials and the target population. We perform simulations to evaluate the bias of conventional random effect models and multiply imputed estimates using the pooled trials sample and describe causal estimators that explicitly address trial-to-target differences in key covariates in the context of systematic missing data. Results indicate that the causal transportability estimators are unbiased when treatment effect modifiers are accounted for in the analyses. Results also highlight the importance of carefully evaluating identifiability conditions for each trial to reduce bias due to differences in participant characteristics between trials and the target population. Bias can be limited by adjusting for covariates that are strongly correlated with missing treatment effect modifiers, including data from trials that do not differ from the target on treatment modifiers, and removing trials that do differ from the target and did not assess a modifier.

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.

Synthesis and Anti-Proliferative Evaluation of Arctigenin Analogues with C-9' Derivatisation.

Dibenzylbutyrolactone lignans (DBLs) are a class of natural products with a wide variety of biological activities. Due to their potential for the development of human therapeutic agents, DBLs have been subjected to various SAR studies in order to optimise activity. Previous reports have mainly considered changes on the aromatic rings and at the benzylic carbons of the compounds, whilst the effects of substituents in the lactone, at the C-9' position, have been relatively unexplored. This position has an unexploited potential for the development of novel dibenzyl butyrolactone derivatives, with previous preliminary findings revealing C-9'-hydroxymethyl analogues inducing programmed cell cycle death. Using the core structure of the bioactive natural product arctigenin, C-9' derivatives were synthesised using various synthetic pathways and with prepared derivatives providing more potent anti-proliferative activity than the C-9'-hydroxymethyl lead compound.

Synthesis and Anti-Proliferative Activity of 5-Benzoyl and 5-Benzylhydroxy Derivatives of 3-Amino-2-Arylcarboxamido-Thieno[2-3-b]Pyridines.

3-Amino-2-arylcarboxamido-thieno[2-3-b]pyridines have been previously described as having potent anti-proliferative activity against MDA-MB-231 and HCT116 cancer cell lines. The mechanism by which these molecules prevent cancer cell growth is proposed to be through interfering with phospholipid metabolism via inhibition of PI-PLC, along with other cellular processes. Previously, 5-cinnamyl derivatives of these thieno[2-3-b]pyridines have been shown to have enhanced anti-proliferative activity compared to compounds lacking this moiety, indicating a tethered aromatic ring is important for this western region of the pharmacophore. Herein, we report the synthesis and biological evaluation of a library of 40 novel thieno[2-3-b]pyridine analogues containing shorter benzoyl or secondary benzyl alcohol tethers at the 5-position, in addition to various substituents on the two phenyl rings present on the molecule. Compounds bearing alcohol functionality had improved efficacy compared to their benzoyl counterparts, in addition to a 2-methyl-3-halogen substitution on the 2-arylcarboxamide ring being important for maximising anti-proliferative activity. The most potent molecules 7h and 7i demonstrated IC50 concentrations of 25-50 nM against HCT116 and MDA-MB-231 cells, a similar level of activity as previous thienopyridine compounds bearing cinnamyl moieties, suggesting that these novel derivatives with shorter tethers were able to maintain potent anti-proliferative activity, while allowing for a more concise synthesis.

Using Virtual Reality to Examine the Association Between Respiratory Sinus Arrhythmia and Adolescent Substance Use.

Early substance use is associated with long-term negative health outcomes. Emotion regulation (ER) plays an important role in reducing risk, but detecting those vulnerable because of ER deficits is challenging. Respiratory sinus arrhythmia (RSA), a biomarker of ER, may be useful for early identification of substance use risk. To examine this, we enrolled 23 adolescents (Mage = 14.0; 56% minority) with and without a history of substance use and collected RSA during a neutral baseline, virtual reality challenge scene, and neutral recovery. ANOVAs indicated that adolescents who reported having used a substance were not different from non-using peers on baseline or challenge RSA but demonstrated lower RSA during recovery. This suggests that adolescents with a history of substance use exhibit slower return to baseline RSA after experiencing a challenging situation compared to non-using peers. RSA, an index of ER, may be useful in identifying adolescents at risk for early substance use.

Sleep disturbance and suicidality in psychiatrically hospitalized adolescents: The role of specific emotion regulation domains.

BACKGROUND: Sleep disturbance is associated with broadband measurements of emotion regulation (ER). The linkage between ER, a multidimensional process, and suicidal ideation and suicide attempt is also documented in theoretical and empirical work. Recent research indicates that distinct profiles of ER are associated with psychiatric outcomes, including adolescent suicidal ideation and attempt. The present study examined whether specific domains of ER would explain the association between sleep disturbance, and ideation and attempt among psychiatrically hospitalized adolescents. METHOD: The sample included 284 adolescents who completed self-report measures on sleep disturbance, ER, suicidal ideation, suicide attempt, and psychiatric symptoms upon inpatient hospitalization. RESULTS: Findings indicated that sleep disturbance was associated with suicidal ideation. Further, a single ER domain (perceived limited access to ER strategies) fully accounted for the significant association between sleep disturbance and suicidal ideation. A reported suicide attempt in the past week was correlated with the nonacceptance of emotional responses, perceived limited access to ER strategies, and emotional clarity, but was not associated with sleep disturbance. DISCUSSION: The current findings highlight the importance of examining narrowband ER and indicate the presence of differential associations between sleep disturbance, ER, and suicide-related outcomes. Findings further elucidate the possible role of impaired cognitive responses to emotional experiences in the co-occurrence of sleep disturbance and youth psychiatric outcomes.

Experimental Verification of the Work Fluctuation-Dissipation Relation for Information-to-Work Conversion.

We study experimentally work fluctuations in a Szilard engine that extracts work from information encoded as the occupancy of an electron level in a semiconductor quantum dot. We show that as the average work extracted per bit of information increases toward the Landauer limit k_{B}Tln2, the work fluctuations decrease in accordance with the work fluctuation-dissipation relation. We compare the results to a protocol without measurement and feedback and show that when no information is used, the work output and fluctuations vanish simultaneously, contrasting the information-to-energy conversion case where increasing amount of work is produced with decreasing fluctuations. Our study highlights the importance of fluctuations in the design of information-to-work conversion processes.

Minimally Dissipative Information Erasure in a Quantum Dot via Thermodynamic Length.

In this Letter, we explore the use of thermodynamic length to improve the performance of experimental protocols. In particular, we implement Landauer erasure on a driven electron level in a semiconductor quantum dot, and compare the standard protocol in which the energy is increased linearly in time with the one coming from geometric optimization. The latter is obtained by choosing a suitable metric structure, whose geodesics correspond to optimal finite-time thermodynamic protocols in the slow driving regime. We show experimentally that geodesic drivings minimize dissipation for slow protocols, with a bigger improvement as one approaches perfect erasure. Moreover, the geometric approach also leads to smaller dissipation even when the time of the protocol becomes comparable with the equilibration timescale of the system, i.e., away from the slow driving regime. Our results also illustrate, in a single-electron device, a fundamental principle of thermodynamic geometry: optimal finite-time thermodynamic protocols are those with constant dissipation rate along the process.

Cooperative synaptic and intrinsic plasticity in a disynaptic limbic circuit drive stress-induced anhedonia and passive coping in mice.

Stress promotes negative affective states, which include anhedonia and passive coping. While these features are in part mediated by neuroadaptations in brain reward circuitry, a comprehensive framework of how stress-induced negative affect may be encoded within key nodes of this circuit is lacking. Here, we show in a mouse model for stress-induced anhedonia and passive coping that these phenomena are associated with increased synaptic strength of ventral hippocampus (VH) excitatory synapses onto D1 medium spiny neurons (D1-MSNs) in the nucleus accumbens medial shell (NAcmSh), and with lateral hypothalamus (LH)-projecting D1-MSN hyperexcitability mediated by decreased inwardly rectifying potassium channel (IRK) function. Stress-induced negative affective states are prevented by depotentiation of VH to NAcmSh synapses, restoring Kir2.1 function in D1R-MSNs, or disrupting co-participation of these synaptic and intrinsic adaptations in D1-MSNs. In conclusion, our data provide strong evidence for a disynaptic pathway controlling maladaptive emotional behavior.

Total Asymmetric Synthesis and Stereochemical Confirmation of (+)- and (-)-Lyoniresinol and Its Deuterated Analogues.

Lyoniresinol and its derivatives are lignans which have been isolated from a plethora of plant species. In addition to exhibiting a range of interesting biological activities including anticancer, anti-inflammatory, antimicrobial, and others, these compounds have also been discovered in wines and spirits and shown to have gustatory effects in these alcoholic matrices. (+)-Lyoniresinol 1 is reported to impart a strong bitter taste while its enantiomer (-)-lyoniresnol 2 is tasteless. The first total asymmetric synthesis of both natural enantiomers (+)-1 and (-)-2 and their deuterated analogues (D4)-(+)-3 and (D4)-(-)-4 has been achieved, confirming the structure and stereochemistry of the natural products. The synthesized compounds can be utilized as internal standards in stable isotope dilution analysis for improving and optimizing the existing lyoniresinol quantitation methods in the future.

The enantioselective total syntheses of (+)-7-oxohinokinin, (+)-7-oxoarcitin, (+)-conicaol B and (-)-isopolygamain.

A flexible approach to C7 keto dibenzyl butyrolactone lignans was developed and the synthesis of several natural products and their related derivatives is described herein. The developed pathway proceeds through enantioenriched ß-substituted butyrolactones, from which facile aldol addition and subsequent oxidation affords the desired benzylic ketone moiety. This methodology was used to complete the first enantioselective total syntheses of three natural products, (+)-7-oxohinokinin, (+)-7-oxoarcitin and (+)-conicaol B, and a further five analogues. The utility of this method was further demonstrated through a 1-2 step modification to access another class of natural product, aryltetralin lignans, allowing the asymmetric total synthesis of (-)-isopolygamain and a polygamain derivative. Anti-proliferative testing determined (-)-isopolygamain was the most active of the compounds prepared, with IC50 values of 2.95 ± 0.61 µM and 4.65 ± 0.68 µM against MDA-MB-231 (triple negative breast cancer) and HCT-116 (colon cancer) cell lines, respectively.

Pretransplant Quality of Life and Post-Transplant Survival in Adolescents with Cystic Fibrosis.

OBJECTIVE: Cystic fibrosis (CF) is the most common indication for pediatric lung transplantation and the third most common for adults. The selection of candidates and timing of transplant is challenging and whether there is a survival benefit of this procedure for pediatric patients is controversial. Use of the Cystic Fibrosis Questionnaire-Revised (CFQ-R), a well-validated, disease-specific quality of life measure may improve pretransplant referral decision-making. METHODS: This multicenter study evaluated whether specific domains on the CFQ-R (i.e., Physical Functioning, Respiratory Symptoms), assessed pretransplant, predicted survival 4-year post-transplant (n = 25). A two-step Cox regression, with physical predictors entered in step one (i.e., age, CF-related Diabetes, FEV1% predicted) and the Physical Functioning and Respiratory Symptoms CFQ-R scales entered in step two, was used to assess whether the CFQ-R explained additional and unique variance. Receiver Operating Characteristic (ROC) curves were used to assess the sensitivity and specificity of optimal cut-points of significant CFQ-R domains. RESULTS: The Respiratory Symptoms scale predicted survival 4-year post-transplant (Exp(B) = 0.38, 95% CI = 0.14-1.01; area under the curve = 0.87) and once it was added to the model, no other individual predictors were significant. The incremental improvement beyond the physical parameters approached but did not reach statistical significance (χ2 Δ = 5.79, p = .06). CONCLUSIONS: This study suggested that including patient-reported outcomes could aid pretransplant referral decision-making. The Respiratory Symptoms scale in particular may serve as a useful tool to help determine when to refer and evaluate an individual for transplant.

Causally Interpretable Meta-analysis: Application in Adolescent HIV Prevention.

Endowing meta-analytic results with a causal interpretation is challenging when there are differences in the distribution of effect modifiers among the populations underlying the included trials and the target population where the results of the meta-analysis will be applied. Recent work on transportability methods has described identifiability conditions under which the collection of randomized trials in a meta-analysis can be used to draw causal inferences about the target population. When the conditions hold, the methods enable estimation of causal quantities such as the average treatment effect and conditional average treatment effect in target populations that differ from the populations underlying the trial samples. The methods also facilitate comparison of treatments not directly compared in a head-to-head trial and assessment of comparative effectiveness within subgroups of the target population. We briefly describe these methods and present a worked example using individual participant data from three HIV prevention trials among adolescents in mental health care. We describe practical challenges in defining the target population, obtaining individual participant data from included trials and a sample of the target population, and addressing systematic missing data across datasets. When fully realized, methods for causally interpretable meta-analysis can provide decision-makers valid estimates of how treatments will work in target populations of substantive interest as well as in subgroups of these populations.