Interplay between interparental relationship quality and infant temperament predicts toddler transdiagnostic psychopathology.

Although exposure to interparental conflict (IPC) in late childhood and adolescence appears to be a robust risk factor for the development of child psychopathology, less work has examined how very early exposure to IPC poses risk for the development of psychopathology in the first 2 years of life. Further, it is unclear whether IPC is uniquely related to child psychopathology relative to other critical dimensions of the interparental relationship. This study aimed to investigate the unique effects of IPC and low levels of emotional intimacy in the interparental relationship during pregnancy and infancy on toddler psychopathology and whether children with higher negative emotionality during infancy were most vulnerable to these conditions. One hundred fifty-one cohabitating couples completed semistructured interviews and questionnaires once during pregnancy and three times postpartum. Results demonstrated that consistent and sustained interparental emotional intimacy, first observed during pregnancy and persisting throughout infancy, was a unique predictor of toddler psychopathology, controlling for sustained and persistent exposure to IPC. The negative association between emotional intimacy and toddler general psychopathology was stronger at higher levels of infant negative emotionality. Results highlight the importance of early exposure to a warm, affectionate interparental relationship for healthy child socioemotional development. These findings have potential for informing early prevention and intervention efforts, including prenatal programs, aimed at reducing psychopathology across the lifespan. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A General Strategy for N-(Hetero)arylpiperidine Synthesis Using Zincke Imine Intermediates.

Methods to synthesize diverse collections of substituted piperidines are valuable due to the prevalence of this heterocycle in pharmaceutical compounds. Here, we present a general strategy to access N-(hetero)arylpiperidines using a pyridine ring-opening and ring-closing approach via Zincke imine intermediates. This process generates pyridinium salts from a wide variety of substituted pyridines and (heteroaryl)anilines; hydrogenation reactions and nucleophilic additions then access the N-(hetero)arylpiperidine derivatives. We successfully applied high-throughput experimentation (HTE) using pharmaceutically relevant pyridines and (heteroaryl)anilines as inputs and developed a one-pot process using anilines as nucleophiles in the pyridinium salt-forming processes. This strategy is viable for generating piperidine libraries and applications such as the convergent coupling of complex fragments.

Early executive control buffers risk for adolescent psychopathology during the COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had a global impact on youth mental health, and there is a critical need for research examining individual factors that contribute to increased psychopathology during the pandemic. The current study explored whether executive control (EC) abilities in early childhood interact with COVID-related stress to attenuate risk for adolescent psychopathology during the first 6 months of the pandemic. METHODS: Participants were 337 youth (49% female) living in a small midwestern city in the United States. Participants completed EC tasks when they were approximately 4.5 years old as part of a longitudinal study investigating cognitive development. At annual laboratory visits during adolescence and before the pandemic, participants (Mage = 14.57) reported on mental health symptoms. In July and August of 2020, participants (Mage = 16.57) reported on COVID-related stress and depression, anxiety, and trauma symptoms. RESULTS: COVID-related stress was associated with increased internalizing problems after controlling for prepandemic symptom levels. Further, the impact of COVID-related stress on adolescent internalizing problems was moderated by preschool EC, with higher levels of EC buffering the effects of COVID-related stress on adolescent internalizing problems. CONCLUSIONS: Findings highlight the importance of promoting EC early in development, as well as screening for EC deficits and implementing targeted intervention strategies across the lifespan to help reduce the impact of stress on adolescent internalizing problems.

Does preschool executive control mediate the impact of early environmental unpredictability and deprivation on the general factor of psychopathology a decade later?

BACKGROUND: Although deprivation has been consistently shown to increase risk for psychopathology through impaired executive control, the unique effects of other dimensions of early adversity, such as unpredictability, on executive control development are poorly understood. The current study evaluated whether deprivation and/or unpredictability early in life have unique effects on the general factor of psychopathology through impaired preschool executive control. METHODS: Participants included 312 children (51% female) oversampled for greater sociodemographic risk. Preschool executive control was measured using a battery of nine developmentally appropriate executive control tasks. Dimensions of adversity were measured with observational and caregiver assessments, and psychopathology was measured with caregiver and child reports. RESULTS: In separate models, both deprivation and unpredictability had significant indirect effects on the adolescent general factor of psychopathology through impaired preschool executive control. However, when both dimensions of adversity were included simultaneously, early life deprivation, but not unpredictability, was uniquely associated with the general factor of psychopathology in adolescence through impaired preschool executive control. CONCLUSIONS: Preschool executive control appears to be a transdiagnostic mechanism through which deprivation, but not unpredictability, increases risk for the general factor of psychopathology in adolescence. Results elucidate potential transdiagnostic targets for intervention efforts aimed at reducing the development and maintenance of psychopathology across the life span.

Feasibility, effectiveness and patient satisfaction of telerehabilitation after thumb carpometacarpal arthroplasty and reverse total shoulder arthroplasty: A pilot study.

INTRODUCTION: Telemedicine is an effective, emerging interface to connect practitioners with patients. It facilitates access to healthcare expertise, reduces costs, time demands and health disparities while improving satisfaction. This pilot study evaluated the feasibility, effectiveness and patient satisfaction of telerehabilitation for thumb carpometacarpal (CMC) arthroplasty and reverse shoulder arthroplasty (rTSA). METHODS: This prospective investigation was performed at a single academic institution with two hand and upper extremity fellowship-trained orthopaedic surgeons. All patients undergoing CMC arthroplasty or rTSA were eligible for inclusion. Telerehabilitation was delivered by a hybrid model including an in-person post-operative visit, followed by alternating in-clinic and virtual videoconference visits. All patients were offered participation in the study arm; those that preferred in-person therapy were included as a control group. Therapy was initiated two weeks post-operative with an in-clinic evaluation. Patients then participated in alternating in-clinic and virtual visits weekly for eight weeks, followed by one virtual visit at 14-weeks post-operative and one clinical visit at 16-weeks post-operative. Patient reported and functional outcomes were collected at each visit. RESULTS: In the CMC group, 19 study and 11 control patients were enrolled. In the rTSA group, five study and 14 control patients were enrolled. No statistically significant differences between telerehabilitation and control for range-of-motion, pain and patient-reported functional outcomes was noted. All patients in the telerehabilitation arms reported high satisfaction. DISCUSSION: Utilizing telehealth in rehabilitation may be a viable option in upper extremity recovery. We hope this pilot programme can be a model for development of future telerehabilitation programmes.

Learning from adversity: What the COVID-19 pandemic can teach us about family resiliency.

The present study aimed to characterize the immediate impacts of the COVID-19 pandemic on families with preschool age children and to identify pre-pandemic factors that explained unique family experiences. We leveraged an ongoing longitudinal study of relatively well-resourced community families who had reported on family functioning prior to the pandemic and completed surveys 6 months after pandemic onset. Both parents of dual parenting households endorsed significant hardships as a direct result of the pandemic (e.g., disrupted family routines, challenges at work); however, families also reported aspects of flourishing (i.e., experiencing positive outcomes in response to adversity) such as spending more time together as a family. Families were prone to greater hardships and fewer opportunities for growth to the extent that parents were lower in psychological resources (i.e., greater stress and internalizing symptoms, poor well-being) and were not on the same page as a couple (i.e., interparental discord, low quality coparenting) prior to pandemic onset. Finally, greater pandemic hardships predicted poorer parental mental health, greater family dysfunction, and elevated child psychopathology, controlling for pre-pandemic levels. Parents who reported more family flourishing from the pandemic had a stronger interparental relationship. Results are intended to inform theories of family stress and family interventions that can be tailored to promote resiliency (i.e., adaptation to challenging life events) and prevent dysfunction when families face rapid change and adjustment and high degrees of uncertainty and stress.

Empirical support for a dual process model of the p-factor: Interaction effects between preschool executive control and preschool negative emotionality on general psychopathology.

Recent work indicates that a general factor, often referred to as the p-factor, underlies nearly all forms of psychopathology. Although the criterion validity and utility of this general factor have been well supported, questions remain about the substantive meaning of the p-factor. The purpose of the present longitudinal study was to empirically test the hypothesis that the p-factor reflects dysregulation arising from a combination of high dispositional negative emotionality and low executive control. The current study examined preschool executive control, measured using a battery of 9 developmentally appropriate executive control tasks, as a moderator of the association between preschool negative emotionality and both concurrent and subsequent levels of general psychopathology in preschool and elementary school using a community sample (N = 497). Latent moderated structural equation models demonstrated that preschool executive control significantly moderated the associations between preschool negative emotionality and general psychopathology both in preschool and approximately 5 years later in elementary school. These results suggest that the general factor of psychopathology may reflect dysregulation arising from a tendency to experience high negative affect, without sufficient executive control to effectively down-regulate that affect. This work has important implications for identifying transdiagnostic targets for prevention and intervention efforts, as well as furthering understanding of the substantive meaning and construct validity of the general factor of psychopathology. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A Diastereoselective Method for the Construction of syn-2'-Deoxy-2'-fluoronucleosides.

A general and diastereoselective fluorination/glycosylation strategy for the synthesis of 2'-fluorinated nucleosides has been developed. Electrophilic fluorination of a glycal with NFSI provided the 1',2'-difunctionalized furanoside intermediate with high diastereoselectivity. The TBS-protected 2'-deoxyfluorosulfonimide sugar was prepared on an 80 g scale and isolated as a crystalline, bench-stable single diastereomer. This intermediate was found to undergo a subsequent glycosylation reaction with a variety of heteroaryl nucleophiles with generally good diastereoselectivities.

A chemoenzymatic strategy for site-selective functionalization of native peptides and proteins.

The emergence of new therapeutic modalities requires complementary tools for their efficient syntheses. Availability of methodologies for site-selective modification of biomolecules remains a long-standing challenge, given the inherent complexity and the presence of repeating residues that bear functional groups with similar reactivity profiles. We describe a bioconjugation strategy for modification of native peptides relying on high site selectivity conveyed by enzymes. We engineered penicillin G acylases to distinguish among free amino moieties of insulin (two at amino termini and an internal lysine) and manipulate cleavable phenylacetamide groups in a programmable manner to form protected insulin derivatives. This enables selective and specific chemical ligation to synthesize homogeneous bioconjugates, improving yield and purity compared to the existing methods, and generally opens avenues in the functionalization of native proteins to access biological probes or drugs.

Diverse Catalytic Reactions for the Stereoselective Synthesis of Cyclic Dinucleotide MK-1454.

As practitioners of organic chemistry strive to deliver efficient syntheses of the most complex natural products and drug candidates, further innovations in synthetic strategies are required to facilitate their efficient construction. These aspirational breakthroughs often go hand-in-hand with considerable reductions in cost and environmental impact. Enzyme-catalyzed reactions have become an impressive and necessary tool that offers benefits such as increased selectivity and waste limitation. These benefits are amplified when enzymatic processes are conducted in a cascade in combination with novel bond-forming strategies. In this article, we report a highly diastereoselective synthesis of MK-1454, a potent agonist of the stimulator of interferon gene (STING) signaling pathway. The synthesis begins with the asymmetric construction of two fluoride-bearing deoxynucleotides. The routes were designed for maximum convergency and selectivity, relying on the same benign electrophilic fluorinating reagent. From these complex subunits, four enzymes are used to construct the two bridging thiophosphates in a highly selective, high yielding cascade process. Critical to the success of this reaction was a thorough understanding of the role transition metals play in bond formation.

Self-compassion mediates the link between attachment security and intimate relationship quality for couples navigating pregnancy.

Millions of couples navigate the transition from pregnancy to postpartum in a given year, and this period of change and adjustment in the family is associated with elevated risk for intimate relationship dysfunction. Self-compassion has the potential to promote skills that are essential for healthy adaptation (e.g., emotion regulation, greater openness and flexibility, and more awareness of the needs of oneself and one's partner). The overarching goal of the present study was to investigate the role of self-compassion in intimate relationship quality during pregnancy. A sample of 159 couples completed semi-structured interviews and questionnaires. Parents engaging in more compassionate self-responding during pregnancy have higher-quality intimate relationships as measured across multiple facets-the degree of emotional intimacy and closeness in the relationship, adaptive conflict management and resolution, high-quality support in response to stress, and a high degree of respect and acceptance directed toward each other. Furthermore, compassionate self-responding emerged as a mediator of the link between attachment security and intimate relationship quality. Specifically, mothers who were higher in attachment anxiety reported lower levels of compassionate self-responding, which in turn undermined multiple dimensions of the intimate relationship. Furthermore, fathers who were higher in attachment avoidance practiced less self-compassion, which have deleterious consequences for the couple. These results provide implications that can inform conceptual frameworks of intimate relationship quality and clinical implications for interventions targeting the transition into parenthood.

Millones de parejas pasan por la transición del embarazo al posparto cada año, y este periodo de cambio y adaptación en la familia está asociado con un riesgo elevado de disfunción en las relaciones amorosas. La autocompasión puede promover habilidades que son fundamentales para una adaptación saludable (p. ej.: regulación emocional, mayor apertura y flexibilidad, mejor conocimiento de las necesidades propias y de las del otro integrante de la pareja). El objetivo general del presente estudio fue investigar el papel que desempeña la autocompasión en la calidad de las relaciones amorosas durante el embarazo. Una muestra de 159 parejas contestó entrevistas y cuestionarios semiestructurados. Los padres con más autorrespuestas compasivas durante el embarazo tuvieron relaciones amorosas de mejor calidad según la evaluación de diferentes aspectos: el grado de intimidad emocional y cercanía en la relación, la gestión adaptativa de conflictos y la resolución de los mismos, el apoyo de alta calidad en respuesta al estrés y un alto grado de respeto y aceptación mutuos. Además, la autorrespuesta compasiva surgió como mediadora del vínculo entre la seguridad del apego y la calidad de las relaciones amorosas. Específicamente, las madres que tuvieron una mayor ansiedad en el apego informaron niveles más bajos de autorrespuesta compasiva, lo cual, a su vez, debilitó varios aspectos de la relación amorosa. Además, los padres que tuvieron una mayor evitación en el apego practicaron menos autocompasión, lo cual tuvo consecuencias perjudiciales para la pareja. Estos resultados tienen implicancias que pueden orientar los marcos conceptuales de la calidad de las relaciones amorosas y consecuencias clínicas para las intervenciones dirigidas a la transición a la paternidad.

Synthesis of a CGRP Receptor Antagonist via an Asymmetric Synthesis of 3-Fluoro-4-aminopiperidine.

A practical and efficient enantioselective synthesis of the calcitonin gene-related peptide receptor antagonist 1 has been developed. The key structural component of the active pharmaceutical ingredient is a syn-1,2-amino-fluoropiperidine 4. Two approaches were developed to synthesize this important pharmacophore. Initially, Ru-catalyzed asymmetric hydrogenation of fluoride-substituted enamide 8 enabled the synthesis of sufficient quantities of compound 1 to support early preclinical studies. Subsequently, a novel, cost-effective route to this intermediate was developed utilizing a dynamic kinetic asymmetric transamination of ketone 9. This synthesis also features a robust Ullmann coupling to install a bis-aryl ether using a soluble Cu(I) catalyst. Finally, an enzymatic desymmetrization of meso-diester 7 was exploited for the construction of the γ-lactam moiety in 1.

Rheological Properties, Dissolution Kinetics, and Ocular Pharmacokinetics of Loteprednol Etabonate (Submicron) Ophthalmic Gel 0.38.

Purpose: To evaluate rheological properties, in vitro dissolution, and in vivo ocular pharmacokinetics of loteprednol etabonate (LE) (submicron) ophthalmic gel 0.38%. Methods: The viscosity of the LE gel 0.38% formulation was measured with a controlled stress rheometer. Dissolution kinetics were evaluated in a fixed-volume and flow-through assay. Rabbits received a single instillation of LE (submicron) gel 0.38% (both eyes), and concentrations of LE in ocular tissues were determined through 24 h by liquid chromatography with tandem mass spectrometry. Where indicated, comparators included micronized LE gel 0.38%, 0.5% (Lotemax® gel), and 0.75%. Results: LE (submicron) gel 0.38% exhibited shear-thinning characteristics similar to LE gel 0.5% with nearly identical yield stress. LE (submicron) gel 0.38% released 2.6-fold more LE into the dissolution medium than micronized LE gel 0.5% over 30 s in the fixed-volume dissolution assay, and submicron LE attained higher concentrations of dissolved LE than micronized LE gel 0.38% in the flow-through dissolution assay. In rabbits, the maximal concentration and area-under-the-curve over 24 h for LE in aqueous humor were 2.5- and 1.8-fold higher, respectively, for LE (submicron) gel 0.38% versus micronized LE gel 0.5% (both P < 0.001). Pharmacokinetic parameters were similar for most other tissues. Conclusions: LE (submicron) gel 0.38% demonstrated similar rheological properties to micronized LE gel 0.5% but faster dissolution, thus providing similar or higher LE concentrations in the aqueous humor, cornea, and iris-ciliary body after ocular dosing in rabbits despite a lowered concentration of drug in the formulation.

Pd-Catalyzed Synthesis of Aryl and Heteroaryl Triflones from Reactions of Sodium Triflinate with Aryl (Heteroaryl) Triflates.

A novel method for Pd-catalyzed triflination of aryl and heteroaryl triflates using NaSO2CF3 as the nucleophile is described. The combination of Pd2(dba)3 and RockPhos formed the most effective catalyst. A broad range of functional groups and heteroaromatic compounds were tolerated under the neutral reaction conditions. The order of reactivity ArOTf ≥ ArCl ≥ ArBr is consistent with transmetalation being a slow step of the reaction.

Rh(I)-Catalyzed Cycloisomerization of 1,6-Enynes.

A new and unexpected Rh(I)-catalyzed cycloisomerization of 1,6-enynes is reported. Several different alkyne substitution patterns were evaluated under the reaction conditions, including a deuterated derivative that provides some insight into the reaction mechanism.

Synthesis of ent-ketorfanol via a C-H alkenylation/torquoselective 6π electrocyclization cascade.

The asymmetric synthesis of ent-ketorfanol from simple and commercially available precursors is reported. A Rh(I) -catalyzed intramolecular CH alkenylation/torquoselective 6π electrocyclization cascade provides a fused bicyclic 1,2-dihydropyridine as a key intermediate. Computational studies were performed to understand the high torquoselectivity of the key 6π electrocyclization. The computational results demonstrate that a conformational effect is responsible for the observed selectivity. The ketone functionality and final ring are introduced in a single step by a redox-neutral acid-catalyzed rearrangement of a vicinal diol to give the requisite carbonyl, followed by intramolecular Friedel-Crafts alkylation.

Catalytic dynamic kinetic resolutions with N-heterocyclic carbenes: asymmetric synthesis of highly substituted ß-lactones.

New DKR type: An N-heterocyclic carbene (NHC)-catalyzed dynamic kinetic resolution of racemic α-substituted ß-keto esters has been developed. This method relies on the epimerization of an NHC-enol intermediate before subsequent aldol/acylation events. Highly substituted ß-lactones are produced in good yield with good to excellent selectivities (see scheme).

Single-molecule surface-enhanced Raman spectroscopy of crystal violet isotopologues: theory and experiment.

Single-molecule surface-enhanced Raman spectroscopy (SMSERS) of crystal violet (CV) has been reported since 1997, yet others have offered alternative explanations that do not necessarily imply SMSERS. Recently, the isotopologue approach, a statistically significant method to establish SMSERS, has been implemented for members of the rhodamine dye family. We provide the first demonstration of SMSERS of a triphenylmethane dye using the isotopologue approach. Two isotopologues of CV are employed to create chemically identical yet vibrationally distinct probe molecules. Experimental spectra were compared extensively with computational simulations to assign changes in mode frequencies upon deuteration. More than 90 silver nanoparticle clusters dosed with a 50:50 mixture of CV isotopologues were spectroscopically characterized, and the vibrational signature of only deuterated or undeuterated CV was observed 79 times, demonstrating that the isotopologue approach for proving SMSERS is applicable to both the CV and the rhodamine systems. The use of CV, a minimally fluorescent dye, allowed direct evaluation of enhancement factors (EF), which are reported herein. Through experiment and theory, we show that molecular electronic resonance Raman (RR) and surface-enhanced Raman effects combine synergistically in SMSERS. Excluding RR effects, the EF(SERS) is ∼10(9). Variations and relationships between substrate morphology and optical properties are further characterized by correlated SMSERS-localized surface plasmon resonance (LSPR)-high-resolution transmission electron microscopy (HRTEM) studies. We did not observe SMSERS from individual nanoparticles; further, SMSERS-supporting dimers are heterodimers of two disparately sized particles, with no subnanometer gaps. We present the largest collection to date of HRTEM images of SMSERS-supporting nanoparticle assemblies.